A Propensity-Score Adjusted Analysis of Clinical Outcomes after Pulmonary Valve Replacement in

Tetralogy of Fallot

Jouke P. Bokma MD1,2; Tal Geva MD3; Lynn A. Sleeper ScD3; Sonya V. Babu-Narayan MB BS BSc

FRCP PhD4; Rachel M. Wald MD5; Kelsey Hickey3; Katrijn Jansen MD5; Rebecca E. Wassall MSc4;

Minmin Lu MS3; Michael A. Gatzoulis MD PhD4; Barbara J.M. Mulder MD PhD1,2; Anne Marie Valente

MD3

1 Department of Cardiology, Academic Medical Center Amsterdam, the Netherlands

2 Netherlands Heart Institute, Utrecht, the Netherlands

3 Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston,

4 Department of Adult Congenital Heart Disease, Royal Brompton Hospital, London, UK

5 Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, Toronto, Ontario,
Canada

Word count: 2953 (excluding references, figure legends and tables)

Corresponding author:

Anne Marie Valente, MD

Boston Children’s Hospital, Department of Cardiology

Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115

E-mail: anne.valente@cardio.chboston.org
Abstract

Objective: To determine the association of pulmonary valve replacement (PVR) with death and

sustained ventricular tachycardia (VT) in patients with repaired tetralogy of Fallot (rTOF).

Methods: Subjects with rTOF and cardiac magnetic resonance (CMR) from an international registry

were included. A PVR propensity score was created to adjust for baseline differences. PVR consensus

criteria were pre-defined as pulmonary regurgitation >25% and ≥2 of the following criteria: right

ventricular (RV) end-diastolic volume >160 mL/m2, RV end-systolic volume >80 mL/m2, RV ejection

fraction (EF)<47%, left ventricular EF<55%, QRS duration>160 ms. The primary outcome included

(aborted) death and sustained VT. The secondary outcome included heart failure, nonsustained VT,

and sustained supraventricular tachycardia.

Results: In 977 rTOF subjects (age 26±15 years, 45% PVR, follow-up 5.3±3.1 years), the primary and

secondary outcome occurred in 41 and 88 subjects, respectively. The hazard ratio (HR) for subjects

with versus without PVR (time-varying covariate) was 0.65 (95% CI:0.31-1.36; p=0.25) for the primary

outcome and 1.43 (95% CI:0.83-2.46; p=0.19) for the secondary outcome after adjusting for

propensity and other factors. In subjects (n=426) not meeting consensus criteria, the HR for subjects

with (n=132) versus without (n=294) PVR was 2.53 (95% CI:0.79-8.06; p=0.12) for the primary

outcome and 2.31 (95% CI:1.07-4.97; p=0.03) for the secondary outcome.

Conclusion: In this large multicenter rTOF cohort, PVR was not associated with a reduced rate of

death and sustained VT at an average follow-up of 5.3 years. Additionally, there were more events

after PVR compared to no PVR in subjects not meeting consensus criteria.

Key words: Congenital Heart Disease; Tetralogy of Fallot; Cardiovascular Magnetic Resonance

Imaging

2
Key questions

 What is already known about this subject?

Pulmonary valve replacement (PVR) is highly effective in treating pulmonary regurgitation and

reducing RV volumes in patients with repaired tetralogy of Fallot (rTOF). However, it is not

known if PVR is also associated with improved clinical outcomes.

 What does this study add?

In this large cohort study, PVR was not associated with a reduced rate of death or sustained

ventricular tachycardia in a propensity-adjusted analysis during approximately 5 years of

follow-up. Additionally, there were more events after PVR in subjects not meeting consensus

criteria for PVR.

 How might this impact on clinical practice?

Our findings suggest a higher event rate after PVR in patients not meeting treatment criteria.

Importantly, this result should be confirmed over a longer period of time to inform timing of this

intervention.

3
Introduction

Pulmonary regurgitation (PR) occurs frequently after surgical repair of tetralogy of Fallot (TOF) and

often leads to right ventricular (RV) dilation.[1] Repaired TOF (rTOF) patients with progressive RV

dilation and dysfunction are at risk for arrhythmias, heart failure, and sudden cardiac death, generally

beginning in the third decade of life.[1,2] Pulmonary valve replacement (PVR) is highly effective in

treating PR and reducing RV volumes in the short-term;[3,4] yet prognostic benefits of PVR have not

been demonstrated in a prospective randomized clinical trial. Moreover, studies comparing outcomes

of PVR versus conservative management in matched cohorts found no clear differences in outcomes.

[5–7] However, these studies were not adequately powered and lacked quantitative assessment of the

RV.[5,6] Consequently, the role and timing of PVR in rTOF remain a subject of debate.[8–10] Current

European and American guidelines suggest PVR in asymptomatic patients with worsening

hemodynamic parameters, but offer no criteria with specific cut-offs to aid in the timing of PVR.[11,12]

Several studies reported preoperative RV volume thresholds to achieve postoperative

normalization of RV volumes and/or function following PVR.[3,4,13] These observations led some

authors to suggest that PVR should be performed early on, utilizing more proactive criteria, to prevent

irreversible RV dysfunction and reduce the risk of arrhythmias.[14,15] On the other hand, PVR is

associated with several late risks including prosthetic valve dysfunction requiring reintervention,[4,16]

and endocarditis.[17] Furthermore, patients remain at risk for RV deterioration and clinical events

during mid-to-late follow-up after PVR.[18,19] Most importantly, patients with limited RV dilation and

dysfunction in the setting of PR, who might be considered for early PVR, are at low risk of adverse

events or progressive RV deterioration when managed conservatively.[20,21] Therefore, optimal

timing and specific criteria for PVR remain unknown.

The objectives of this study were to determine the association of PVR with freedom from major

adverse outcomes in patients with rTOF and to explore whether there might be a clinical benefit in

patients who receive PVR according to consensus guidelines.

4
Methods

Subjects:

A detailed description of the International Multicenter TOF Registry (INDICATOR), including

recruitment protocol, inclusion and exclusion criteria, and data collection and analysis in the core

laboratory has been published.[22] Briefly, subjects were included by participating centers using the

following inclusion criteria: (1) repaired TOF; (2) cardiovascular magnetic resonance (CMR) completed

between 1997 and 2010; (3) 12-lead electrocardiogram (ECG) within 1 year from CMR; and (4) clinical

follow-up ≥1 year or occurrence of a primary outcome. INDICATOR is being updated at regular

intervals and more patients have been included since the trial design and original paper.[20,22]

Additional inclusion criteria for this analysis included: (1) CMR measurable RV volumes from cine

steady-state free precession (available since 2002), (2) no history of PVR prior to qualifying CMR, and

(3) in subjects who underwent PVR (surgical or percutaneous), CMR within 3 years prior to surgery.

Subjects who had experienced sustained ventricular tachycardia (VT) or aborted sudden death prior to

the qualifying CMR were excluded. Follow-up began at the date of the qualifying CMR. Each

participating center received Institutional Review Board or Ethics Committee approval.

Data collection:

For the INDICATOR registry, de-identified data were sent to the data-coordinating center, which

included a data repository, CMR core laboratory, and a statistical core.[22] Each participating center

updated clinical events until last hospital visit or death, including clinical events that occurred after

PVR, using case report forms. A 1.5-Tesla MR imaging scanner was used for CMR studies by

participating centers using a similar imaging protocol.[22] De-identified digital copies of the CMR

examinations were sent to the CMR core laboratory for analysis.[22] For all CMRs performed, RV and

left ventricular (LV) volumes and mass were measured in the ventricular short-axis plane as described

by Alfakih et al.[23] Biventricular stroke volumes and ejection fractions (EF) were calculated. Volumes

were adjusted for both body surface area (BSA) and BSA 1.3, to account for variances across a

population that includes pediatric patients, as previously reported.[24]

Consensus Guideline Criteria for PVR:

Predefined guideline criteria for PVR were characterized as ‘proactive’ or ‘conservative’ approaches

based on available literature and by consensus of authors (Table 1). These approaches were then

used to examine potential associations between PVR and the defined outcomes within guidelines

5
subgroup (criteria met/not met).[13,18,20,25]

In a total of 252 subjects with missing PR fraction, and one with missing body mass index,

PVR-criteria status could not be obtained. All 170 subjects with PR fraction <25% were classified as

not meeting PVR-criteria.

Outcomes:

The composite primary outcome consisted of all-cause mortality, aborted sudden cardiac death, or

sustained VT (defined as VT lasting >30 s or requiring cardioversion). The composite secondary

outcome consisted of advanced heart failure class (NYHA III or IV), nonsustained VT (<30 s), or

sustained supraventricular tachycardia (ectopic atrial tachycardia, atrial flutter or atrial fibrillation). For

both outcomes, the time to the earliest occurring component defined the time to qualifying event.

Propensity score:

A propensity score for PVR was created to adjust for baseline differences between PVR and non-PVR

subjects (see Supplementary Tables 1,2 and table notes). A logistic regression model with PVR as the

outcome was used to generate propensity scores for all subjects. Variables that are potential

arguments for PVR (site, age at repair, era of repair (before or after 1980), age at CMR, RV end-

diastolic volume (EDV)/BSA, RV end-systolic volume (ESV)/BSA, RV mass/volume, RV EF, LV EF,

QRS duration) were included in the model. All variables in the propensity model were available in

>95% of subjects: mean or simple regression imputation was used for missing variables

(Supplementary Table 2).

Statistical analysis:

Categorical data were described as number with frequency and continuous data as median with

interquartile range (IQR) or mean with standard deviation, as appropriate. Differences in baseline

characteristics between PVR and non-PVR subjects and subjects with and without primary and

secondary outcome were analyzed by independent samples t-test, Wilcoxon rank sum test, Fisher

exact test, or chi-square test, as appropriate. Time to the occurrence of the primary and secondary

outcomes was analyzed using multivariable Cox hazards regression analysis with PVR (time-

dependent) and propensity score as covariates. In addition, other variables related to the outcome

(e.g., arrhythmias) after stepwise forward selection were included as time-dependent covariates in the

survival model. A secondary analysis was performed using 1:1 matching on propensity score, with

difference in score of less than 0.09 (a quarter of the mean difference) between PVR and non-PVR

6
pairs. A frailty failure time model was used to estimate the association of PVR with outcomes in the 1:1

matched cohort, with adjustment for other risk factors.  The frailty model takes the matched design into

account by assuming correlation between events within the same pair, rather than assuming

independence. Differential association between predefined guideline (proactive and conservative)

criteria status and PVR with respect to the primary and secondary outcomes was examined in subjects

for whom data regarding PVR-criteria were available, using a test of interaction between PVR criteria

(met/not met) and PVR status (time-dependent).

Statistical analyses were performed using SAS version 9.3 (SAS Institute, Cary, NC) and R

version 3.2.1. A two-sided P-value <0.05 was considered to indicate statistical significance.

Results

Of the 1358 subjects enrolled in the INDICATOR cohort, 977 met the study inclusion criteria

(Figure 1)(Table 2). A total of 440 subjects underwent PVR (396 (90%) surgical, 44 (10%)

percutaneous) 1.02 ± 0.87 years after the qualifying CMR. There were 3 patients with the primary

outcome (2 deaths, 1 sustained VT) within 1 month after PVR. Compared with subjects who did not

undergo PVR, those who did were younger at first repair and at CMR, had larger BSA-indexed

ventricular volumes, lower mass-to-volume ratio, lower RV and LV EF, and longer QRS duration

(online Supplementary Table 1). The propensity score differentiated adequately (C-statistic 0.85)

between subjects with PVR (mean 0.65 ± 0.24) and those without PVR (mean 0.29 ± 0.23)(online

Supplementary Table 2).

Primary outcome:

Of the 977 subjects, 41 (4%) experienced the primary outcome during mean follow-up of 5.3 ±

3.1 years. Of those, 30 died (sudden cardiac in 5, heart failure in 3, cardiac other in 1, non-cardiac

other in 9, and unknown in 12), 6 experienced sustained VT, and 5 had resuscitated sudden cardiac

death. Of the 41 subjects who experienced the primary outcome, 15 had PVR prior to the outcome,

and 26 did not. Table 2 summarizes factors associated with the primary outcome. When PVR and

propensity score were forced into the final multivariable model, the hazard ratio (HR) for the PVR

group was 0.65 (95% CI: 0.31, 1.36; p=0.25) (Table 3a), suggesting a non-significantly lower event

rate of the primary outcome after adjusting for other factors. In a propensity score-matched analysis, a

total of 512 subjects (256 PVR and 256 non-PVR) were included. A total of 184 PVR subjects (with 8

7
events) could not be matched due to higher propensity score. After correction for atrial arrhythmia, RV

EF, and RV mass/volume, there was a non-significantly lower event rate after PVR in the matched

cohort (HR 0.63; 95% CI: 0.25, 1.62; p=0.34)(Table 3b).

Subjects with rTOF and RV-PA conduit (n=162, 17%) had different clinical characteristics than

those without a conduit, including increased primary outcome rates (HR 2.34; 95% CI: 1.21, 4.53;

p=0.01 in univariate analysis), less PR (mean 28 ± 15% versus 37 ± 17%, p<0.001), and increased RV

mass-to-volume ratio (0.31 ± 0.13 versus 0.21 ± 0.07, p<0.001). However, in the full cohort, the

association of PVR with the primary outcome was similar in subjects with RV-PA conduit compared to

those without (interaction p=0.88).

Secondary outcome:

A total of 93 subjects who had a history of heart failure (New York Heart Association (NYHA)

class III-IV), atrial arrhythmia or nonsustained VT prior to the qualifying MRI were excluded from the

secondary outcome analysis. Of the 884 subjects included in the secondary outcome analysis, 88

experienced the outcome (6 had heart failure, 25 atrial flutter, 7 atrial fibrillation, and 50 experienced

nonsustained VT) during follow-up. The secondary outcome occurred in 44 of the 393 PVR subjects

(34 occurred after PVR) and in 44 of the 491 non-PVR subjects.

In univariate analysis, PVR was associated with a higher hazard of the secondary outcome

(HR 1.66; 95% CI: 1.07, 2.60; p=0.03). After correcting for propensity score and additional covariates,

the higher hazard of event in PVR subjects was no longer statistically significant (HR: 1.43; 95% CI:

0.83, 2.46; p=0.19)(online Supplementary Table 3a). A propensity score-matched cohort (418

subjects) revealed similar results (covariate-adjusted HR: 1.28 for PVR-group; 95% C.I. 0.65, 2.54;

p=0.48)(online Supplementary Table 3b).

Timing of PVR:

In an analysis of the potential clinical benefit according to predefined criteria, 724 subjects with

data to assess guideline criteria experienced 25 primary outcomes. A total of 32 subjects with

PR<25% underwent PVR, presumably for RV outflow tract obstruction, and were classified as not

meeting proactive or conservative criteria. Of 724 subjects, 41% met the proactive criteria definition

and 23% met the conservative criteria definition.

The association between PVR and the primary outcome did not vary according to meeting

versus not meeting either conservative or proactive criteria subgroup (interactions p=0.17 and p=0.28,

8
respectively)(Figure 2). However, we found non-significantly higher event rates after PVR when

conservative criteria (HR 1.92, 95% CI: 0.66, 5.61, p=0.23) or proactive criteria (HR 2.53, 95% CI:

0.79, 8.06, p=0.12) were not met and no significant difference when criteria were met (Figure 2).

For the analysis of PVR criteria and the secondary outcome, 655 subjects were included and

experienced 61 secondary outcomes. Patterns were similar to those for the primary outcome (Figure

2). Although there was low statistical power to detect a differential impact of PVR in subjects who did

and did not meet guidelines criteria (i.e., non-significant interaction terms, p=0.09 for conservative and

p=0.36 for proactive criteria), there were subgroup findings of clinical interest. In subjects who did not

meet conservative criteria, there was a higher hazard of the secondary outcome after PVR compared

to no PVR (HR 2.35; 95% CI: 1.24, 4.44; p=0.009). In contrast, there was no association between

PVR and the secondary outcome when conservative criteria were met (HR 0.91; 95% CI: 0.35, 2.39;

p=0.85). Similarly for proactive criteria, there was no significant difference in secondary outcome

events rates after PVR compared to no PVR when criteria were met, and there was a higher event

rate after PVR when criteria were not met (HR 2.31, 95% CI: 1.07, 4.97, p=0.03). These findings were

robust to adjustment for propensity score and other relevant covariates.

Discussion

In this large multicenter cohort of mostly young adults with repaired tetralogy of Fallot, PVR was not

associated with a reduced risk for adverse clinical outcomes during a follow-up period of 5.3±3.1

years. In exploratory analysis investigating different strategies of PVR-timing, we found a weak,

statistically non-significant signal suggesting a lower rate of death/sustained VT in patients meeting

conservative criteria. Our results underscore the observation that the rate of death or sustained VT in

this population is low and even a large cohort such as INDICATOR is insufficient to provide conclusive

evidence to support a proactive versus a conservative approach to PVR. Specifically, it is conceivable

that with a substantially larger cohort and longer follow-up, evidence of treatment benefit or harm may

emerge.

Our results are in line with several, smaller previous reports, in which PVR was not associated

with improved outcomes.[5–7] Other studies observed more supraventricular tachyarrhythmias

following PVR (15% vs 6%)[5] and an increased rate of nonsustained VT after percutaneous Melody

implantation.[26]

9
 To our knowledge, the finding that ‘early’ PVR, in patients not yet fulfilling proactive criteria,

was associated with increased risk of heart failure, atrial arrhythmia, and nonsustained VT has not

been previously reported. One may speculate that the higher event rate is due to several factors: (1)

patients without PVR with similar hemodynamic status had a very low clinical event rate, suggesting

there is no clear clinical need for valve implantation. In these patients, RV function may be sufficient to

maintain adequate cardiac output; (2) although PVR reduces RV volumes, its effects on RV EF,

dyssynchrony, and fibrosis in patients with a modest disease burden are likely small or non-existent.

[4,27,28] These factors may be more important determinants of clinical outcomes in patients with

limited RV dilation; (3) surgery is associated with risks[4] and may have detrimental short-term impact

on RV function.[29] Furthermore, myocardial incisions may also create new arrhythmia substrates; and

(4) bioprosthetic valves used for PVR typically deteriorate over time,[16] which may be associated with

progressive RV dilatation and dysfunction,[19] with likely multiple reinterventions needed in patients

with early referral for PVR as observed in this cohort. Percutaneous PVR may avoid some of these

factors, but hemodynamic response is likely similar. The number of patients with percutaneous PVR

was still limited in our study; future studies may investigate whether a percutaneous approach may

alter timing of PVR.[17,26]

It is worth noting that our study aimed to evaluate clinical outcome after PVR compared to no

PVR. Although we observed no statistically significant differences, we did not determine the effect of

PVR on subjective symptoms or exercise capacity.[4] PVR can be considered in patients with

symptoms attributed to RV volume overload, according to current guidelines.[10–12]

The outcomes of different PVR-timing strategies should be confirmed over a longer period of

time, as the beneficial hemodynamic effects of PVR may translate into better clinical outcomes after a

longer follow-up duration.[4,18] Clinically significant (35% reduction in risk in the overall cohort),

although not statistically significant, trends after 5 years of follow-up may suggest that beneficial

effects of PVR in the more severely affected patients (fulfilling conservative criteria) could manifest

after a longer period than in our study. However, this needs to be evaluated in future studies as

unfavorable effects of bioprosthetic valve deterioration, endocarditis, and reinterventions are also likely

to increase in the PVR group.[16–19]

Limitations

10
This study is limited by its observational cohort design. Although we employed propensity score

adjustment to minimize bias in causal inferences, such inferences should still be treated with caution,

and ideally validated in a randomized trial. The cohort is further restricted to subjects who have

undergone CMR; this limitation is partially mitigated by the routine use of CMR in this patient group at

the participating centers. However, inclusion of subjects with CMR allowed correction for baseline

differences using a PVR propensity score. The PVR propensity score was also used to account for

differences between centers in referral for PVR. The event rate was low (4% for the primary outcome),

which limits statistical power, particularly for the detection of differential associations of PVR and

outcome according to treatment guidelines subgroup. An additional limitation is that there is no

standardized protocol for diagnostic testing at these centers. Specifically, exercise testing and

echocardiography were not available in many subjects, and PR fraction data was missing in some. We

could not ascertain whether PS or endocarditis was also present in some patients, but sensitivity

analysis excluding patients with limited (<25%) PR revealed similar results. We did not investigate

PVR according to symptoms as this is recommended by current guidelines and not necessarily

dependent on clinical benefits.[11,12] Because this is one of the largest cohorts available for this

population, we have presented all subgroup effect estimates with their confidence intervals and p-

value for use in future hypothesis generation, regardless of interaction test results.

Conclusions

In this large multicenter, cohort of patients with repaired tetralogy of Fallot with an average follow-up of

5.3 years, PVR was not associated with a reduced risk for adverse clinical outcomes, including death

and sustained VT. With regard to different strategies of PVR timing, we found more clinical events if

PVR was performed without meeting consensus treatment criteria, but this result should be confirmed

over a longer period of time to inform optimal timing for this intervention.

11
Funding:

This work was supported by the Netherlands Heart Institute (NL-HI) and Nuts Ohra foundation. The

work described in this study was carried out in the context of the Parelsnoer Institute. Parelsnoer

Institute is part of and funded by the Dutch Federation of University Medical Centers. This work was

also supported by the Higgins Family Noninvasive Research Fund at Boston Children’s Hospital, the

Lerner Research, NIH/NHLBI 1 R01 HL089269-01A2, and British Heart Foundation (SVB-N;

FS/11/38/28864). SVB-N, REW and MAG were supported by the NIHR Cardiovascular Biomedical

Research Unit of Royal Brompton and Harefield NHS. RMW was supported by the Canadian Institutes

of Health Research MOP 119353. Foundation Trust and Imperial College London. This report is

independent research by the National Institute for Health Research Biomedical Research Unit Funding

Scheme.

Conflicts of interest:

None declared

The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all

authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to

the BMJ Publishing Group Ltd and its Licensees to permit this article (if accepted) to be published in

HEART editions and any other BMJPGL products to exploit all subsidiary rights

12
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doi:10.1053/j.jvca.2012.10.022

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Figure legends

Figure 1: Inclusion flow-chart

Flow-chart of all subjects included in the INDICATOR cohort and reasons for excluding for analysis in

the present study, divided according to PVR status. Abbreviations: CMR: cardiovascular magnetic

resonance, PVR: pulmonary valve replacement.

Figure 2: Event rate according to proactive and conservative criteria and PVR status

Event rates according to prespecified PVR and proactive/conservative criteria subgroups. *: The PVR

propensity corrected hazard ratio of event (PVR compared to no PVR) for all patients is displayed as

the overall estimate for the primary and secondary outcome. The unadjusted hazard ratio of event

within subgroups are also displayed in this figure including the interaction test p-value. Abbreviations:

HR: hazard ratio, PVR: pulmonary valve replacement.

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Table 1: Consensus guideline criteria for PVR

Subjects with PR ≥25% and ≥2 of the following criteria: Proactive Conservative

RV EDV / BSA (mL/m2) >160 mL/m2 >180 mL/m2

RV ESV / BSA (mL/m2) >80 mL/m2 >95 mL/m2

RV EF (%) <47% <40%

LV EF (%) <55% <45%

QRS duration (ms) >160 ms >180 ms

Table 1: In overweight subjects (body mass index >35 kg/m 2): RV/LV EDVi ratio >2 considered as

fulfilling criterion. Abbreviations: BSA: body surface area, EF: ejection fraction, EDV: end-diastolic

volume, ESV: end-systolic volume, LV: left ventricle, RV: right ventricle

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 Table 2. Baseline characteristics according to primary outcome (death/VT) status

Overall Death/VT No Outcome P-value

(n=977) (n=41) (n=936)

Male 536 (54.9%) 21 (51.2%) 515 (55.0%) 0.74

TOF with PA or AV canal 170 (17.4%) 11 (26.8%) 159 (17.0%) 0.10

Additional cardiovascular anomaly 385 (39.4%) 20 (48.8%) 365 (39.0%) 0.25

Associated genetic disorder 290 (29.7%) 16 (39.0%) 274 (29.3%) 0.33

Median age at repair, years (IQR) 2.5 (0.5, 6.1) 5.7 (1.7, 17.3) 2.4 (0.5, 6.0) <.001

First repair era <1980 309 (31.6%) 23 (56.1%) 286 (30.6%) 0.008

QRS duration (ms) 144±27 155±30 143±27 0.01

PVR (prior to outcome) 440 (45%) 15 (37%) 425 (45%) 0.72

Rhythm Abnormalities (at any time)

Supraventricular arrhythmias 147 (15.0%) 15 (36.6%) 132 (14.1%) <.001

Atrial flutter 74 (7.6%) 10 (24.4%) 64 (6.8%)

Atrial fibrillation 36 (3.7%) 8 (19.5%) 28 (3.0%)

Atrial tachycardia 85 (8.7%) 6 (14.6%) 79 (8.4%)

Nonsustained VT 103 (11.0%) 14 (34.1%) 89 (9.9%) <.001

Pacemaker 15 (1.5%) 0 (0%) 15 (1.6%)

Implantable defibrillator 46 (4.7%) 11 (26.8%) 35 (3.7%) 0.002

CMR parameters

Age at CMR (years) 26.4±14.5 36.7±19.8 25.9±14.0 <.001

RV EDV / BSA (mL/m2) 152.8±50.3 160.9±65.1 152.4±49.5 0.07

RV ESV / BSA (mL/m2) 79.7±35.9 97.4±49.8 79.0±35.0 <.001

RV EF (%) 49.1±8.6 41.8±10.8 49.4±8.3 <.001

RV mass:volume ratio (g/mL) 0.23±0.09 0.28±0.18 0.23±0.08 0.009

LV EDV / BSA (mL/m2) 86.4±20.5 91.1±30.1 86.2±20.0 0.04

LV ESV / BSA (mL/m2) 37.0±13.7 45.3±24.5 36.6±13.0 <.001

LV EF (%) 58.0±7.4 52.9±10.6 58.2±7.1 <.001

LV mass:volume ratio (g/mL) 0.62±0.16 0.67±0.21 0.62±0.15 0.38

Table 2: Baseline characteristics of subjects included in the present study, stratified according to the

primary outcome status. Mean and standard deviation or frequency and percentage are presented
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unless otherwise specified. Abbreviations: AV: atrioventricular, BSA: body surface area, CMR:

cardiovascular magnetic resonance, EF: ejection fraction, EDV: end-diastolic volume, ESV: end-

systolic volume, LV: left ventricle, PA: pulmonary atresia, PR: pulmonary regurgitation, PVR:

pulmonary valve replacement, RV: right ventricle, VT: ventricular tachycardia

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 Table 3a: Multivariable Cox regression model of primary outcome in full cohort (N=977; 41
events)

Predictor HR 95% CI p-value

PVR 0.65 0.31, 1.36 0.25

Propensity score 2.51 0.64, 9.83 0.19

Age at first repair (per year) 1.05 1.01, 1.09 0.007

RV EF (per 1%) 0.92 0.89, 0.96 <.001

Atrial arrhythmia 2.42 1.16, 5.04 0.02

Nonsustained VT 2.66 1.33, 5.33 0.006

Table 3b: Multivariable Cox regression model of primary outcome in 1:1 matched cohort (N=512;
23 events)

Predictor HR 95% CI p-value

PVR 0.63 0.25, 1.62 0.34

RV EF (per 1%) 0.91 0.86, 0.96 <.001

Atrial arrhythmia 3.94 1.57, 9.86 0.003

RV mass:volume (per 0.1 increase) 1.41 1.00, 1.98 0.05

Table 3: Multivariable Cox Regression analysis for the primary outcome in full cohort (table 3a) and in

the cohort matched 1:1 on propensity score (table 3b). Abbreviations: EF: ejection fraction, PVR:

pulmonary valve replacement, RV: right ventricle, VT: ventricular tachycardia

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