Download 1 Survival in Childhood Pulmonary Arterial

Survival in Childhood Pulmonary Arterial Hypertension:
Insights From the Registry to Evaluate Early and Long-term PAH Disease Management
Running title: Barst et al.; Survival in Childhood PAH
Robyn J. Barst, MD1; Michael D. McGoon, MD2; C. Gregory Elliott, MD3;
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Aimee J. Foreman, MA4; Dave P. Miller, MS4; D. Dunbar Ivy, MD5
Columbia University College of Physicians and Surgeons, New York, NY; 2Mayo Clinic,
Rochester, MN; 3Intermountain Medical Center and The University of Utah, Murray, UT; 4ICON
Clinical Research, San Francisco, CA; 5University of Colorado Denver, Denver, CO
1
Correspondence:
Robyn J. Barst, MD
Columbia University
College of Physicians and Surgeons
31 Murray Hill Road
Scarsdale, NY 10583, USA
Tel: (914) 582-9002
Fax: (914) 723-0099
E-mail: [email protected]
Journal Subject Code: [18] Pulmonary circulation and disease
1
Abstract:
Background - Pulmonary arterial hypertension (PAH) is a rare but important cause of morbidity
and mortality in children.
Methods and Results - We analyzed data from 216 patients aged ”18 years at diagnosis enrolled
in the Registry to EValuate Early And Long-term PAH disease management (REVEAL). Median
age at diagnosis and enrollment was 7 and 15 years, respectively. The most frequent presenting
symptom was dyspnea (idiopathic/familial PAH [IPAH/FPAH], 53%; PAH associated with
congenital heart disease [APAH-CHD], 30%). Presyncope/syncope was more frequent in
patients with IPAH/FPAH (36%) than APAH-CHD (4%). At diagnosis, mean pulmonary arterial
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pressure and pulmonary vascular resistance index (PVRI) were 56 mmHg and 17 Wood
units*m2, respectively. Five-year survival from diagnosis for the overall cohort was 74%±6%
with no significant difference between the IPAH/FPAH (n=122; 75%±7%) and APAH-CHD
(n=77; 71%±13%) cohorts (P=0.53). Older age at diagnosis was the only variable significantly
associated with decreased survival from diagnosis. Variables at enrollment that were
significantly associated with decreased survival from enrollment included higher PVRI, lower
weight z-scores, and FPAH. Additional variables at enrollment, identified in a secondary
analysis, that were marginally associated with increased survival from enrollment included acute
vasoreactivity (adaptation of conventional pediatric definition; P=0.087) and lower brain
natriuretic peptide (P=0.060). None of the 22 patients who were acute responders treated with
high-dose calcium channel blockade as monotherapy or combination therapy died within 5 years
of diagnosis.
Conclusions - Utilizing the REVEAL Registry, we identified key predictors of survival in
childhood PAH. Refining these prognostic parameters should help clinicians improve outcomes.
Clinical Trial Registration Information - ClinicalTrials.gov; Identifier: NCT00370214
Key words: hypertension, pulmonary; pediatrics; registries; survival
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Introduction
Pulmonary arterial hypertension (PAH), an important cause of morbidity and mortality, is
characterized by increased pulmonary vascular resistance (PVR) and pulmonary artery pressure
(PAP).1 With an estimated prevalence of 15–50 cases/million among adults, PAH is a rare
disease.2 PAH is even less common in children, with an estimated prevalence of <10
cases/million.3 Treatment options for children with PAH have been extrapolated from evidencebased adult guidelines. Although the clinical features and course may differ at times between
pediatric and adult PAH patients, limited data suggest that the use of medications approved for
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the treatment of adults favorably affects children with PAH.4 Additionally, recent observational
studies have identified prognostic parameters for adults with PAH;5 however, prognostic
indicators in children are poorly understood. To date, the literature on pediatric PAH has been
primarily limited to relatively small sample sizes from single centers. A broader description of
current clinical characteristics, treatment patterns, and outcomes of childhood PAH is not yet
available to inform physicians.
The Registry to EValuate Early And Long-term PAH disease management (REVEAL) is a large
observational study of children and adults diagnosed with PAH at medical centers distributed
across the four major census regions of the United States. In contrast to clinical trials that are
often only several months in duration and have restrictive enrollment criteria, the REVEAL
registry aims to provide long-term observations of a broader PAH patient population. In this
article, we describe demographic and hemodynamic characteristics, treatment, and survival of
children diagnosed with PAH who are enrolled in REVEAL.
3
Methods
Study Design and Population
The design and baseline characteristics of REVEAL have been described previously.4,6 Pediatric
patients (aged •3 months and ”18 years at diagnosis) were followed at 26 of the 55 REVEAL
sites. REVEAL was initiated prior to the 4th World Symposium on Pulmonary Hypertension;7,8
accordingly, patient categorization conforms to the 3rd World Symposium on Pulmonary
Hypertension.9 Study objectives and methods were prespecified in an Institutional Review
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Board-approved protocol, and all participants or their legal guardians gave written informed
consent (and assent as appropriate).
Inclusion Criteria
PAH was defined as mean pulmonary artery pressure (mPAP) •25 mmHg at rest, pulmonary
capillary wedge pressure (PCWP) ”15 mmHg, and PVR •3 Wood units. The date of diagnosis
was defined as the date of the right heart catheterization (RHC) confirming these criteria. Both
newly diagnosed (diagnostic RHC within 3 months prior to enrollment) and previously
diagnosed patients were enrolled. Patients were categorized by PAH subgroups: idiopathic PAH
(IPAH); familial PAH (FPAH); PAH associated with: connective tissue disease (APAH-CTD),
congenital heart disease (APAH-CHD; repaired or unrepaired), human immunodeficiency virus
(APAH-HIV), portal hypertension (APAH-PoPH), and drugs/toxins (APAH-drugs/toxins); and
persistent pulmonary hypertension of the newborn (PPHN). Descriptive statistics for treatments
at enrollment exclude patients in blinded trials for whom treatment data was not collected.
4
We examined two definitions of acute vasoreactivity: (1) the adult consensus definition, agreed
upon at the 3rd and 4th World Symposia:10 decrease in mPAP •10 mmHg reaching <40 mmHg,
with an increase or no change in cardiac output (CO); and (2) an adaptation of the conventional
pediatric criteria:11,12 decrease in mPAP •20%, an increase or no change in cardiac index (CI),
and a decrease or no change in the PVR to systemic vascular resistance ratio, which we modified
to allow for clinically insignificant decreases in CI. Standardized z-scores for weight and height
were derived using age- and sex-based standards from the National Center for Health Statistics.13
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Statistical Analysis
Descriptive statistics are provided for subgroup comparisons, including number and percentage
of non-missing values for categorical data and mean ± standard deviation for continuous
variables. Medians, rather than means, were reported for continuous variables with a skewed
distribution. Pulmonary and systemic blood flows were calculated using the Fick method (with
oxygen consumption estimated by the method of LaFarge and Miettinen) for patients with
APAH-CHD with unrepaired or partially repaired lesions. For all other patients, either Fick or
thermodilution methods were used.
P values for descriptive group comparisons were obtained using Fisher’s exact test. The twosample t test was used where data were approximately normally distributed, and the two-sample
Wilcoxon rank-sum test was used for variables that were not normally distributed. Two-year
Kaplan-Meier survival estimates (± standard error) from enrollment were calculated for
subgroups, and P values were obtained using log-rank. P values were calculated for hazard ratios
(HRs) for IPAH/FPAH versus APAH-CHD from Cox proportional hazard models. Patients who
5
had undergone transplant were not censored, and follow-up continued post-transplant. A
secondary analysis was performed with the endpoint of transplant-free survival.
Five-year Kaplan-Meier survival estimates from time of diagnostic RHC, accounting for left
truncation,14 were calculated for the combined IPAH/FPAH and APAH-CHD subgroups, and for
each of these two subgroups separately. Left truncation arises when patient information is
gathered retrospectively. When the outcome of a study is survival from diagnosis, many patients
may not have been enrolled in the study until months or years after diagnosis. By having
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survived to enrollment, these patients could not have had an event between diagnosis and
enrollment, and therefore are removed from the risk set between those two time points.
The impact of candidate predictors of survival from the time of diagnostic RHC and from the
time of enrollment was examined using Cox proportional hazards models. Proportional-hazards
assumptions were confirmed with a Kolmogorov-type supremum test.15 Survival models from
time of diagnostic RHC accounted for left truncation. All variables with individual P values
<0.20 were entered into a stepwise multivariable Cox regression to include a broad range of
variables. Multiple imputation was used to fill in missing data for candidate predictors in the
multivariable models and generate valid statistical estimates of error.16
Results
Patient Characteristics
Twenty-six sites followed 216 consecutively enrolled children with PAH confirmed by RHC.
Newly and previously diagnosed patients were enrolled from March 2006 to September 2007
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with additional newly diagnosed patients consecutively enrolled through December 2009. The
data lock was November 19, 2010.
The IPAH/FPAH and APAH-CHD subgroups combined accounted for 199 (92%) of the total
216 patients (IPAH/FPAH, n=122; APAH-CHD [repaired, n=29; unrepaired/partial repair,
n=48]). The remaining 8% were divided among the other Group I PH subgroups: APAH-CTD
(n=10), APAH-PoPH (n=3), PPHN (n=3), and other APAH (n=1). Of the 199 patients in the
IPAH/FPAH and APAH-CHD subgroups, 108 (54%) were diagnosed after 2001, 58 (29%) were
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diagnosed from 1995–2001, and 33 (17%) were diagnosed before 1995. These divisions are
based on eras of PAH drug availability in the United States. No PAH-specific drugs were
approved prior to 1995, epoprostenol was the only approved drug from 1995–2001, and
additional drugs have been approved since 2001. A total of 30 patients (14%) were newly
diagnosed at enrollment.
Demographics
Demographic characteristics of the patients stratified by subgroup are shown in Table 1. Overall,
64% were female. The most frequent initial presenting symptom in both subgroups was dyspnea
on exertion (IPAH/FPAH, 53%; APAH-CHD, 30%). Presyncope/syncope was more frequent in
IPAH/FPAH patients compared with APAH-CHD patients (36% vs 4%, respectively; P<0.001).
The median time from onset of symptoms to diagnostic RHC was 8 months for both the APAHCHD and IPAH/FPAH cohorts. Fifty-two percent of children with available data were New York
Heart Association/World Health Organization (NYHA/WHO) functional class (FC) I or II at
time of diagnosis.
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Hemodynamic Parameters
Hemodynamic data are presented in Table 2. The patients had marked elevations in mean arterial
pressure (MAP) and PVR index (PVRI) that were higher for IPAH/FPAH versus APAH-CHD
(MAP: 73±17 vs 68±14 mmHg, respectively; P=0.044; PVRI: 19±17 vs 13±9 Wood units*m2,
respectively; P=0.014). Mean right atrial pressure (mRAP) was not elevated in either the
IPAH/FPAH or APAH-CHD patients. CI was normal in 39% of the IPAH/FPAH patients and
53% of APAH-CHD.
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Acute Vasoreactivity
Between the IPAH/FPAH (n=122) and APAH-CHD (n=77) patients, 162 underwent acute
vasodilator testing (AVT). Utilizing the adaptation of the conventional pediatric definition,11,17
36/102 (35%) IPAH/FPAH children were acute responders (FPAH, 5/13) versus 9/60 (15%) for
APAH-CHD patients (P=0.006). Among the 36 IPAH/FPAH responders, 8 were receiving longterm calcium channel blockers (CCBs) for PAH as monotherapy at enrollment, and 6 were
receiving CCBs as part of combination therapy. Among the 9 APAH-CHD responders, 3 were
treated with CCBs as monotherapy at enrollment and 3 with CCBs as part of combination
therapy. Using the adult consensus definition,10,18,19 19/102 (19%) IPAH/FPAH patients were
acute responders (FPAH, 2/13) versus 4 of 60 patients (7%) with APAH-CHD (P=0.038). CCB
monotherapy for PAH was reported at enrollment for 5 of the 19 patients with IPAH/FPAH and
for 2 of the 4 APAH-CHD patients. CCB combination therapy was reported at enrollment for 4
of the 19 IPAH/FPAH patients and 2 of the 4 APAH-CHD patients.
8
Among the 43 patients who were receiving CCBs for PAH at enrollment, either as monotherapy
or as part of combination therapy, 42 (98%) had undergone AVT while 1 (2%) had not. Of those
42 who underwent AVT and were on CCBs, 13 (31%) were acute responders with the adult
consensus definition and 22 (52%) were acute responders according to the adaptation of the
conventional pediatric definition (this includes 23 patients by either definition, 12 of whom were
acute responders with both definitions). At enrollment, the 13 acute responders with the adult
consensus definition included 7 patients treated with CCBs alone and 6 patients treated with
CCBs as part of combination therapy. Among the 22 acute responders (adaptation of
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conventional pediatric definition), 13 were treated with CCB monotherapy at enrollment and 9
with CCB as part of combination therapy at enrollment.
Treatments
A breakdown of PAH treatments at enrollment is shown in Table 3. Phosphodiesterase type-5
(PDE-5) inhibitors were prescribed for 64% of IPAH/FPAH patients versus 45% of APAH-CHD
patients (P=0.012). Prostacyclin analogues were used in 50% of IPAH/FPAH patients versus
28% of APAH-CHD patients (P=0.004). More APAH-CHD patients were on monotherapy
(49%) than dual (24%) or triple therapy (5%), while a similar proportion of IPAH/FPAH patients
were on either monotherapy (37%) or dual therapy (35%); 16% were on triple therapy.
Survival
There were 6 transplantations and 27 deaths (including 3 post-transplant) among the 199 patients
in the IPAH/FPAH and APAH-CHD cohorts. There were 4 deaths among the 17 patients not
included in the IPAH/FAPH and APAH-CHD cohorts (CTD, 2; PoPH, 2). Median follow-up in
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the entire cohort was 42 months (range, 0–51 months) with 1-, 3-, and 5-year estimated survival
rates from diagnostic RHC of 96%±4%, 84%±5%, and 74%±6%, respectively (Figure 1).
Survival within the 5 years after diagnostic RHC was similar between IPAH/FPAH and APAHCHD (75%±7% vs 71%±13%; P=0.53; Figure 5). Five-year survival from diagnostic RHC for
repaired and unrepaired CHD was 60%±19% and 83%±14%, respectively. The findings in the
secondary analysis of transplant-free survival were similar to those of the overall 5-year survival.
The large standard error for the APAH-CHD subgroup and very large standard errors for the
additional stratification of the APAH-CHD subgroup reflects limited sample size available for
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estimating the critical first year of the survival curve. There were no statistically significant
differences in outcomes between incident and prevalent patients. None of the 22 patients that
were acute responders according to the adaptation of the conventional pediatric definition treated
with CCBs as monotherapy or as part of combination therapy died during the first 5 years after
diagnostic RHC. One additional surviving patient was an acute responder only by the adult
consensus definition and was on a medical regimen that included a CCB.
Two-year survival from enrollment for the IPAH/FPAH and APAH-CHD cohorts (n=199) was
88%±2%, and was similar for IPAH/FPAH and APAH-CHD (P=0.60 for time to event; two-year
survival estimated as 90%±3% vs 85%±4%; Figure 2). Two-year survival from enrollment was
also similar for APAH-CHD repaired versus unrepaired/partially repaired (P=0.77 for time to
event; two-year survival estimated as 86%±7% vs 85%±5%; Figure 3). However, when
comparing IPAH and FPAH, two-year survival from enrollment appeared better for IPAH versus
FPAH (P=0.045 for time to event; two-year survival estimated as 92%±3% vs 71%±12%; Figure
4).
10
Univariable Cox proportional hazards regression models of estimated survival from diagnostic
RHC or from enrollment are presented in Table 4. Variables assessed at diagnostic RHC that
were associated with increased mortality from diagnostic RHC (P<0.10) were older age, lower
CI, higher PVRI, and lack of AVT response (as defined by adaptation of original pediatric
definition). Stepwise multivariable analysis identified only older age at diagnostic RHC
(HR=1.51 per 5 years of age; P=0.006) as a predictor of increased mortality from diagnostic
RHC. A sensitivity analysis of the most common PAH subgroups (IPAH/FPAH; APAH-CHD)
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also identified lower height z-scores as a prognostic parameter. Estimates of survival from
enrollment were based on the most recent measurements prior to enrollment, which included the
diagnostic RHC for those patients who did not have a subsequent RHC before enrollment
(75/199; 38%). Predictors of increased mortality from the stepwise enrollment multivariable
model were higher PVRI (HR=1.15 per 5 Wood units*m2; P<0.001), lower weight z-score
(HR=0.71; P=0.005), and FPAH (HR=3.22; P=0.043). In a secondary analysis in which marginal
predictors were included in the model, low BNP <50 pg/mL or N-terminal pro-BNP <300 pg/mL
(HR=0.38; P=0.060) and acute vasoreactivity (HR=0.32; P=0.087, using the adaptation of the
conventional pediatric definition) suggest utility as prognostic parameters of decreased mortality.
The results are similar when excluding the 17 patients not in the IPAH/FPAH or APAH-CHD
subgroups (ie, APAH-CTD, APAH-PoPH, PPHN, and other APAH). Two of the three patients
with APAH-PoPH died; PoPH was not considered a candidate variable in the model because of
the small sample size.
11
Discussion
The pediatric REVEAL cohort is the most comprehensive prospective database of Group 1
childhood PAH reported to date. The size of the study (n=216), number of referral sites (n=26),
and geographical distribution make the observations generalizable to clinical US practice. Fiveyear survival from diagnostic RHC was 74%, considerably better than historical controls in
pediatric PAH,1,12,20,21 and consistent with other recent reports.12,20,22,23 Survival from diagnostic
RHC in the pediatric REVEAL cohort was similar for IPAH/FPAH and APAH-CHD, in contrast
to natural history data that Eisenmenger Syndrome patients had a far better survival than IPAH.24
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Prospective, long-term, observational studies reflecting current practice should help us evaluate
whether the reduction of difference in survival between IPAH/FPAH and APAH-CHD is due to
treatment differences between these two subgroups.
Despite educational efforts for earlier diagnosis, a significant delay persists from onset of
symptoms to diagnosis. The most frequent initial symptom was dyspnea on exertion; however,
this was only reported in 53% of patients with IPAH/FPAH and in even less in those with
APAH-CHD (30%). The two most frequent initial complaints in APAH-CHD, dyspnea on
exertion and fatigue, may not have been significant concerns to the parents because these
symptoms had “always been present” and were thus thought to represent “normal” behavior. Presyncope/syncope was the second most frequent symptom (36%) at presentation in the
IPAH/FPAH cohort. However, the frequency of presyncope/syncope in the APAH-CHD cohort
was only 4%.
12
Although all children had significant PAH at presentation, they rarely presented with right-sided
heart failure or significant limitations affecting activities of daily living. Accordingly, at
diagnosis, half of the patients were FC I or II with normal right heart function. These findings are
in marked contrast to the adults in REVEAL.4 Consistent with these observations, exercise
capacity, assessed by the six-minute walk test, was often within normal range for the children
and greater than in adults with similarly increased mPAP and PVRI.
We found a significant increase in mortality from the time of diagnostic RHC among older
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children (ie, those diagnosed at a later age had a worse prognosis). Aside from age at diagnosis,
the strongest predictors of increased mortality from the time of diagnostic RHC were lower CI,
higher PVRI, and lack of an acute response with AVT (adaptation of conventional pediatric
definition). Previous studies have reported that younger age at diagnosis and acute vasoreactivity
at both diagnosis and at follow-up are prognostic for children with IPAH/FPAH.12,23 Pediatric
data from the UK has recently reported novel prognostic parameters: low weight and height
(growth retardation) predict a poor outcome.25 In addition, van Loon et al reported that worse FC
(ie, higher FC), higher mPAP to MAP ratio, higher BNP, higher uric acid, lower CI, and lower
systolic blood pressure at diagnosis are prognostic.22 Reassessment of disease severity on
treatment has also been shown to be important in assessing prognosis in adults.26
For patients with a positive AVT response, consideration of long-term high-dose CCB therapy is
recommended by both adult and pediatric consensus guidelines.19,27 However, the likelihood of
an acute response in adults with IPAH/FPAH is <10%, and even less frequent for FPAH.28,29 In
contrast, acute vasoreactivity is significantly higher in children: the acute response rate was 35%
13
in the REVEAL pediatric IPAH/FPAH cohort, consistent with the 40% response rate reported by
Yung et al;23,29 thus, performing AVT in children remains important since acute responders can
do extremely well on long-term high-dose CCBs as either monotherapy or as part of combination
PAH therapy. None of the 22 responders treated with CCB as monotherapy or as part of
combination therapy died within 5 years after diagnosis, consistent with the 97% 5-year survival
rate reported by Yung et al; however, the 10-year survival rate was 81%, reinforcing the need to
follow these patients closely long-term. The REVEAL pediatric data suggest that using the
adaptation of the conventional pediatric definition for an acute responder appears to be the most
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reasonable approach at this time to determine who should be considered for initial treatment with
long-term high-dose CCB, and for identifying patients who appear more likely to have a
favorable outcome. These data also suggest that the most recent adult consensus definition for
defining an acute responder to AVT may fail to identify some children who could do extremely
well with long-term CCB either as monotherapy or as part of combination therapy. This
important observation needs confirmation.
A limitation of this study is that most of the patients belong to either the IPAH/FPAH subgroup
or the APAH-CHD subgroup; insufficient data are available to confidently state that our findings
for the overall REVEAL pediatric PAH cohort apply equally well to rare subgroups in pediatric
PAH such as APAH-PoPH. This registry also includes a survival bias, as most of the patients
were previously diagnosed. Thus, the characterization of the population and estimated survival
from enrollment are directly generalizable only for previously diagnosed patients or a population
such as REVEAL and those seen commonly in clinical practice where newly diagnosed patients
are a minority. The estimated survival from diagnostic RHC, which employs a delayed entry
14
model, is applicable to newly diagnosed patients. Interpretation of treatments is limited by the
uncontrolled nature of any registry. Nevertheless, the large sample size, broad representation,
and longitudinal follow-up should prove invaluable. Finally, because only a relatively few deaths
occurred (n=31 out of the total 216 patients), this limited our ability to identify prognostic
parameters, and restricted the primary multivariable analysis to only three predictors. However,
this should not rule out other parameters as unimportant in predicting outcomes; further research
will be critical to confirm or refute the findings of our sensitivity analyses, which included
parameters that, although not statistically significant at this time, may turn out to be statistically
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significant with longer follow-up and an inevitable increase in events.
Based on the observations from the REVEAL pediatric cohort, we identified key predictors of
survival in childhood PAH. Refining these parameters should help clinicians improve outcomes
for their pediatric patients. The REVEAL registry should also increase disease awareness and
facilitate earlier referral to an experienced pediatric center. With recent adult data supporting
early treatment,30 we hope that by seeing children earlier and starting treatment sooner, we will
make further progress in improving outcomes for pediatric PAH.
Acknowledgments: Kathryn Leonard and Jennifer M. Kulak, PhD, of inScience
Communications, a Wolters Kluwer business, provided editorial assistance. The authors wish to
thank the Principal Investigators and their Study Coordinators for their participation in the
REVEAL Registry: David Badesch, MD, University of Colorado Health Sciences Center,
Aurora, CO, and Cheryl Abbott, RNC, PRA; Erika Berman-Rosenzweig, MD, Columbia
University, New York, NY, and Katherine Lee, RN; Sif Hansdottir, MD, University of Iowa
Hospitals & Clinics, Iowa City, IA, and Page Scovel, RN, BSN; Monica Colvin-Adams, MD,
University of Minnesota Medical Center, Fairview, Minneapolis, MN, and Nonyelum Harcourt;
Curt Daniels, MD, Children’s Research Institute at Ohio State, Columbus, OH, and Julianne
Williamson-Mueller, RN, BSN; Curt Daniels, MD, Ohio State University, Columbus, OH, and
15
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Jami Holzaepfel; Raed Dweik, MD, Cleveland Clinic Foundation, Cleveland, OH, and Jennie
Newman; Greg Elliott, MD, Intermountain Medical Center and the University of Utah, Salt Lake
City, UT, and Natalie Kitterman, RN, BSN; Harrison Farber, MD, Boston University School of
Medicine, Boston, MA, and Kim Tobin Finch; Robert Frantz, MD, Mayo Clinic College of
Medicine, Rochester, MN, and Louise Durst, RN; Adaani Frost, MD, Baylor College of
Medicine, Houston, TX, and Helena Purl, RN, BSN; Dunbar Ivy, MD, Children’s Hospital
Department of Cardiology, Aurora, CO, and Kathleen Miller-Reed, RN; George Mallory, MD,
Texas Children’s Hospital, Houston, TX, and Ann Bogran, RN, BSN; Catherine Markin, MD,
Legacy Clinic Northwest, Portland, OR, and Lisa Roessel, RN, FNP, ARNP-BC; Michael
Mathier, MD, University of Pittsburgh School of Medicine, Pittsburgh, PA, and Yvette Mallory;
Dana McGlothlin, MD, UCSF Medical Center, San Francisco, CA, and Erin Kobashigawa;
Donald Moore, MD, Children’s Hospital at Vanderbilt, Nashville, TN, and Mary Beth Boyd,
RN, BSN; Ivan Robbins, MD, Vanderbilt University Medical Center, Nashville, TN, and Tracy
Oyler, RN; Robert Schilz, DO, PhD, University Hospital of Cleveland, Cleveland, OH, and
Dave Haney, RRT; Shelley Shapiro, MD, PhD, VA Greater Los Angeles Health System, Los
Angeles, CA, and Glenna Traiger, RN, MSN; Darren Taichman, MD, PhD, University of
Pennsylvania Medical Center, Philadelphia, PA, and Mamta J. Patel, RN, BSN; Jose Tallaj, MD,
University of Alabama at Birmingham, Birmingham, AL, and Rachel Culbreth, CCRC; Victor
Test, MD, UCSD Medical Center, La Jolla, CA, and Luis Santana, CCRC; James White, MD,
PhD, University of Rochester Medical Center, Rochester, NY, and Karen Frutiger, RN, BSN;
Delphine Yung, MD, Seattle Children’s, Seattle, WA, and Anne Davis, RN; Roham Zamanian,
MD, Stanford University Medical Center, Palo Alto, CA, and Val Scott, RN.
Funding Sources: Funding for the REVEAL Registry is provided by Actelion Pharmaceuticals
US, Inc.
Conflict of Interest Disclosures: Robyn J. Barst, MD, serves as a consultant for and has
received honoraria from Actelion, Bayer, GlaxoSmithKline, GeneraMedix, Gilead, Eli Lilly &
Co., MondoBIOTECH, NIH/NHLBI, Novartis, and Pfizer. Dr. Barst has provided expert
testimony on diet pill litigation for the plaintiffs and has also received grants from Actelion,
Gilead, Eli Lilly & Co., NIH/NHLBI, Novartis, Pfizer, and United Therapeutics. Dr. Barst has
received honoraria for her service on the REVEAL Steering Committee, which is supported by
Actelion. The University of Colorado receives salary support for D. Dunbar Ivy, MD, to serve as
a consultant for Actelion, Gilead, Pfizer, and United Therapeutics. Michael D. McGoon, MD,
serves as a consultant with Actelion, Gilead, Lung Rx, and Medtronic. Dr McGoon has received
grants from Gilead and Medtronic. Dr McGoon has received honoraria for his service on the
REVEAL Steering Committee, which is supported by Actelion. C. Gregory Elliott, MD, is
employed by Intermountain Healthcare. Intermountain Healthcare, with Dr. Elliott as Principal
Investigator, has received grant support during the last 5 years from Actelion, Pfizer, Encysive
Pharmaceuticals, and United Therapeutics. Dr. Elliott has received honoraria for service on the
REVEAL Steering Committee, which is supported by Actelion. Aimee J. Foreman, MA, and
Dave P. Miller, MS, are employed by ICON Clinical Research, a company that receives research
support from Actelion and other pharmaceutical companies. D. Dunbar Ivy, MD, serves as a
consultant for Actelion, Gilead, Pfizer, and United Therapeutics.
16
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19
Table 1. Patient Characteristics*
Characteristic
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Age at diagnosis, median,§ years
Age at enrollment, median,§ years
Female, n (%)
Newly diagnosed, n (%)
Race, n (%)
White
Black
Hispanic
Other
WHO/NYHA FC at PAH diagnosis, n (%)
I
II
III
IV
WHO/NYHA FC at enrollment,|| n (%)
I
II
III
IV
Time from onset of initial symptoms to PAH diagnosis
n
Median,§ months
Acute vasoreactivity (adult definition),n (%)
Acute vasoreactivity (adaptation of conventional pediatric
definition),#** n (%)
6MWD at enrollment,†† m
N
Mean±SD
Initial symptoms attributed to PAH, n (%)
Abdominal distension
Chest pain/discomfort
Cough
Dizziness/lightheadedness
Overall PAH
(N=216)
7
15
139 (64)
30 (14)
IPAH/FPAH
(n=122)
8
15
73 (60)
20 (16)
APAH-CHD
(n=77)
5
15
53 (69)
7 (9)
Other PAH†
(n=17)
17
17
13 (77)
3 (18)
148 (70)
16 (8)
32 (15)
17 (8)
82 (68)
14 (12)
15 (13)
9 (8)
58 (76)
1 (1)
10 (13)
7 (9)
8 (47)
1 (6)
7 (41)
1 (6)
10 (7)
65 (45)
54 (37)
17 (12)
7 (7)
38 (40)
41 (43)
10 (10)
2 (5)
19 (51)
12 (32)
4 (11)
1 (8)
8 (62)
1 (8)
3 (23)
41 (22)
97 (51)
46 (24)
7 (4)
28 (26)
52 (48)
26 (24)
3 (3)
9 (14)
39 (59)
16 (24)
2 (3)
4 (25)
6 (38)
4 (25)
2 (13)
207
9
23/175 (13)
47/175 (27)
118
8
19/102 (19)
36/102 (35)
72
8
4/60 (7)
9/60 (15)
17
16
0/13 (0)
2/13 (15)
154
435±124
97
447±124
45
405±115
12
450±142
3 (1)
26 (12)
11 (5)
23 (11)
2 (2)
20 (16)
7 (6)
18 (15)
0 (0)
2 (3)
1 (1)
1 (1)
1 (6)
4 (24)
3 (18)
4 (24)
20
P Value‡
<0.001
>0.99
0.23
0.20
–
0.050
–
–
–
–
0.64
–
–
–
–
0.26
–
–
–
–
–
0.38
0.038
0.006
–
0.058
–
–
0.52
0.002
0.15
0.001
Characteristic
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Dyspnea at rest
Dyspnea on exertion
Edema
Fatigue
Presyncope/syncope
Raynaud’s phenomenon
Palpitations
Seizures
No reported symptoms
Prior diagnosis of asthma,‡‡ n (%)
Overall PAH
(N=216)
19 (9)
100 (46)
12 (6)
52 (24)
51 (24)
4 (2)
15 (7)
5 (2)
9 (4)
8 (4)
IPAH/FPAH
(n=122)
9 (7)
64 (53)
8 (7)
30 (25)
44 (36)
0 (0)
9 (7)
4 (3)
4 (3)
5 (4)
APAH-CHD
(n=77)
9 (12)
23 (30)
3 (4)
16 (21)
3 (4)
0 (0)
6 (8)
1 (1)
5 (7)
2 (3)
Other PAH†
(n=17)
1 (6)
13 (77)
1 (6)
6 (35)
4 (24)
4 (24)
0 (0)
0 (0)
0 (0)
1 (6)
P Value‡
0.32
0.002
0.53
0.61
<0.001
–
>0.99
0.65
0.31
0.52
*Among patients enrolled in the Registry to EValuate Early And Long-term pulmonary arterial hypertension (PAH) disease management through December 2009 with
pulmonary capillary wedge pressure ”15 mmHg at any time from PAH diagnosis up to enrollment, age ”18 years at PAH diagnosis, and Group I diagnosis of PAH
associated with congenital heart disease (APAH-CHD), idiopathic PAH (IPAH), or familial PAH (FPAH); †Other PAH: PAH associated with connective tissue disease
(n=10), PAH associated with portal hypertension (n=3), persistent pulmonary hypertension of the newborn (n=3), and PAH associated with hereditary hemorrhagic
telangiectasia (n=1); ‡P values are calculated using Fisher's exact test for categorical data and two-sample t tests assuming equal variances for continuous variables, unless
otherwise noted. The P values assess only the two-group comparison between APAH-CHD and IPAH/FPAH; §P values are calculated using the Wilcoxon-Mann-Whitney
test for continuous variables, which do not follow an approximate normal distribution; || New York Heart Association (NYHA) functional class (FC) at enrollment will be
provided if data is available for at least 50% of patients in the table; #The adult consensus definition of acute vasoreactive response is defined as a decrease in mean
pulmonary artery pressure (mPAP) of at least 10 mmHg to a peak vasoreactivity value <40 mmHg, combined with an increase or no change in cardiac output. Four out of
60 APAH-CHD patients and 19 out of 102 IPAH/FPAH patients who underwent acute vasodilator testing were acute responders using the adult consensus definition; **The
adaptation of the conventional pediatric definition of an acute vasoreactive response is defined as a decrease in mPAP of at least 20% and an increase or no change in
cardiac index (CI) and a decrease or no change in the pulmonary to systemic vascular resistance ratio. Unlike the adult definition criteria, decreases in CI are permitted if
the value remains within normal limits (2.5–4.0 L/min/m2) and the decrease in CI is not clinically significant. Nine out of 60 patients with APAH-CHD and 36/102 patients
with IPAH/FPAH were acutely vasoreactive according to the adaptation of the original pediatric definition; ††Seven patients with APAH-CHD and 30 patients with
IPAH/FPAH had available data for 6-minute walk test distance (6MWD) at diagnosis; ‡‡These patients were identified as having a diagnosis of asthma at the time of PAH
diagnosis. SD, standard deviation; WHO, World Health Organization.
21
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Table 2. Hemodynamic Parameters at Diagnostic Right-Sided Heart Catheterization*
Parameter (Mean±SD, n)
Overall PAH
IPAH/FPAH
APAH-CHD
(N=216)
(n=122)
(n=77)
mRAP, mmHg
7±4, 206
7±4, 116
7±3, 74
mPAP, mmHg
56±18, 215
58±19, 121
55±17, 77
MAP, mmHg
72±17, 172
73±17, 92
68±14, 68
mPAP to MAP ratio
0.8±0.3, 172
0.8±0.3, 92
0.8±0.2, 68
SPAP, mmHg
81±24, 203
83±26, 112
80±23, 75
SBP, mmHg
94±19, 168
97±19, 91
88±16, 66
SPAP to SBP ratio
0.9±0.3, 163
0.9±0.3, 86
0.9±0.2, 66
mPCWP,§ mmHg
9±3, 215
9±3, 121
9±3, 77
||
2
Pulmonary blood flow, L/min/m
4±3, 174
4±2, 100
5±5, 61
Systemic blood flow, || L/min/m2
4±2, 173
4±2, 100
4±2, 60
2
PVR index, Wood units*m
17±15, 180
19±17, 104
13±9, 63
SVR index, Wood units*m2
21±13, 139
24±15, 75
17±10, 56
PVR to SVR ratio
0.8±0.5, 155
0.8±0.3, 82
0.8±0.7, 62
SVO2,# %
67±11, 147
68±10, 93
66±8, 41
Other PAH†
(n=17)
7±4, 16
48±11, 17
84±23, 12
0.6±0.2, 12
70±14, 16
104±25, 11
0.7±0.2, 11
8±3, 17
3±1, 13
3±1, 13
15±8, 13
28±12, 8
0.6±0.2, 11
64±19, 13
P Value‡
0.51
0.30
0.044
0.59
0.37
0.002
0.37
0.69
0.015
0.17
0.014
0.002
0.44
0.29
Time of diagnosis was defined as date of confirmatory right-sided heart catheterization. *Among patients enrolled in the Registry to EValuate Early And
Long-term pulmonary arterial hypertension (PAH) disease management through December 2009 with mean pulmonary capillary wedge pressure (mPCWP)
”15 mmHg at any time from PAH diagnosis up to enrollment, age <19 years at PAH diagnosis, and Group I diagnosis of PAH associated with congenital
heart disease (APAH-CHD), idiopathic PAH (IPAH), or familial PAH (FPAH); †Other PAH: PAH associated with connective tissue disease (n=10), PAH
associated with portal hypertension (n=3), persistent pulmonary hypertension of the newborn (n=3), and PAH associated with hereditary hemorrhagic
telangiectasia (n=1); ‡P values are calculated using two-sample t tests assuming equal variances. The P values assess only the two-group comparison
between CHD and IPAH/FPAH; §mPCWP at rest if available, otherwise left ventricular end-diastolic pressure at rest; ||Pulmonary and systemic blood flow
are calculated from the Fick equation for patients with unrepaired CHD shunts or for those with residual shunts. For all others, pulmonary and systemic
blood flow are equal, ie, cardiac index, and were calculated by either Fick or thermodilution; #For patients with APAH-CHD with unrepaired/partial lesion,
SVO2 = O2 saturation proximal to shunt. All others, SVO2 = myocardial oxygen consumption. MAP, mean arterial pressure; mPAP, mean pulmonary artery
pressure; mRAP, mean right-sided atrial pressure; PVR, pulmonary vascular resistance; SBP, systolic blood pressure; SD, standard deviation; SPAP,
systolic pulmonary artery pressure; SVO2, mixed venous oxygen saturation; SVR, systemic vascular resistance.
22
Table 3. Pulmonary Arterial Hypertension (PAH) Treatments at Enrollment*
PAH Treatment, n
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Prostacyclin analogue§
IV epoprostenol
IV treprostinil
Inhaled iloprost
Inhaled treprostinil
SC treprostinil
Oral treprostinil
PDE-5 inhibitor||
Sildenafil
Tadalafil
Endothelin receptor antagonist (ERA)#
Ambrisentan
Bosentan
Sitaxsentan**
Calcium channel blocker (CCB) for PAH††
CCB monotherapy
CCB as part of combination therapy‡‡
No PAH therapy (including no CCB for PAH)
Treated prior to enrollment
Treated after enrollment
Never treated
Monotherapy,§§
Dual therapy,§§
Triple therapy,§§
*
Overall PAH
(N=211)
89 (42%)
33
28
18
0
11
0
121 (57%)
117
4
90 (43%)
0
79
11
43 (20%)
21
22
11 (5%)
2
6
3
87 (41%)
63 (30%)
28 (13%)
IPAH/FPAH
(n=119)
59 (50%)
22
19
13
0
6
0
76 (64%)
73
3
53 (45%)
0
45
8
24 (20%)
10
14
3 (3%)
1
2
0
44 (37%)
42 (35%)
19 (16%)
APAH-CHD
(n=75)
21 (28%)
5
7
5
0
4
0
34 (45%)
33
1
30 (40%)
0
27
3
15 (20%)
8
7
8 (11%)
1
4
3
37 (49%)
18 (24%)
4 (5%)
Other PAH†
(n=17)
9 (53%)
6
2
0
0
1
0
11 (65%)
11
0
7 (41%)
0
7
0
4 (24%)
3
1
0 (0%)
0
0
0
6 (35%)
3 (18%)
5 (29%)
P Value‡
0.004
–
–
–
–
–
–
0.012
–
–
0.55
–
–
–
>0.99
–
–
0.024
–
–
–
0.1
0.11
0.038
Among patients in the Registry to EValuate Early And Long-term PAH disease management enrolled through December 2009 with pulmonary capillary wedge pressure
”15 mmHg at any time from PAH diagnosis to enrollment, age <19 years at PAH diagnosis, and Group I diagnosis of PAH associated with congenital heart disease
(APAH-CHD), idiopathic PAH (IPAH), or familial PAH (FPAH). Five patients on blinded clinical trials at enrollment are excluded; †Other PAH: PAH associated with
connective tissue disease (n=10), PAH associated with portal hypertension (n=3), persistent pulmonary hypertension of the newborn (n=3), and PAH associated with
hereditary hemorrhagic telangiectasia (n=1); ‡P values are calculated using the Fisher’s exact test and assess only the two-group comparison between APAH-CHD and
IPAH/FPAH. §Percent of all children with APAH-CHD or IPAH/FPAH receiving prostacyclin analogues at enrollment; ||Percent of all children with APAH-CHD or
IPAH/FPAH on phosphodiesterase type-5 (PDE-5) inhibitors at enrollment; #Percent of all children with APAH-CHD or IPAH/FPAH on ERAs at enrollment; **Patients
were on sitaxsentan at enrollment but were all transitioned off sitaxsentan in 2007; ††Six out of the 15 children with APAH-CHD and 14 of the 24 children with
IPAH/FPAH on CCBs at enrollment were acute responders to acute vasodilator testing (AVT) at PAH diagnosis (adaptation of conventional pediatric definition). Fifteen of
the 60 children with APAH-CHD and 23 of the 102 children with IPAH/FPAH who underwent AVT at diagnosis were acute responders (adaptation of conventional
pediatric definition); ‡‡Percent of all children with APAH-CHD or IPAH/FPAH receiving CCBs in combination with any other PAH treatment (prostacyclin analogues,
PDE-5 inhibitors, and/or ERAs); §§Percent of children with APAH-CHD or IPAH/FPAH on one, two, or three different PAH therapies at enrollment, where PAH therapies
are defined as any medication displayed in this table except CCBs. IV, intravenous; SC, subcutaneous.
23
Table 4. Cox Proportional Hazards Model of Survival*
Variable
From Diagnostic RHC†
From Enrollment†
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N
HR
95% CI
P Value
N
HR
95% CI
P Value
Age (per 5 years)
215
1.51
(1.13, 2.03)
0.006
215
1.19
(0.99, 1.43)
0.069
Female
215
1.48
(0.67, 3.26)
0.33
215
1.31
(0.60, 2.85)
0.49
‡
215
2.56
(0.82, 7.98)
0.11
215
2.55
(0.85, 7.69)
0.096
APAH-CHD‡
215
1.22
(0.55, 2.68)
0.63
215
1.24
(0.58, 2.66)
0.57
NYHA/WHO FC III/IV§
145
1.60
(0.70, 3.69)
0.27
190
1.98
(0.92, 4.26)
0.082
mPAP to MAP ratio (per 0.1 unit change)
171
0.97
(0.81, 1.16)
0.71
170
1.23
(1.06, 1.44)
0.008
Cardiac indexŒ
175
0.64
(0.45, 0.90)
0.011
173
0.65
(0.45, 0.94)
0.023
154
0.97
(0.85, 1.12)
0.71
145
1.11
(1.01, 1.22)
0.027
179
1.10
(1.02, 1.20)
0.016
166
1.14
(1.06, 1.22)
<0.001
SBP (per 10 mmHg change)
167
1.11
(0.85, 1.44)
0.45
168
0.91
(0.71, 1.17)
0.46
Acute vasoreactivity – adult definition**††
174
0.26
(0.03, 2.08)
0.21
174
0.35
(0.05, 2.60)
0.30
Acute vasoreactivity – adaptation of conventional
174
0.27
(0.06, 1.17)
0.080
174
0.29
(0.07, 1.24)
0.094
IPAH/FPAH with history of presyncope/syncope‡‡
215
0.43
(0.13, 1.41)
0.16
215
0.43
(0.13, 1.40)
0.16
Z-scores for weight
188
0.92
(0.76, 1.11)
0.37
195
0.80
(0.64, 1.01)
0.057
Z-scores for height
181
0.86
(0.69, 1.06)
FPAH
PVR to SVR ratio (per 0.1 unit change)
2
PVR index (per 5 Wood units·m change)
#
**††
pediatric definition
0.16
185
0.83
(0.64, 1.09)
0.18
BNP <50 or NT-proBNP <300 pg/mL at enrollment
§§
§§
–
215
0.35
(0.13, 0.90)
0.030
BNP >180 or NT-proBNP >1500 pg/mL at enrollment
§§
§§
–
215
1.50
(0.46, 4.93)
0.51
Newly vs previously diagnosed PAH at enrollment
§§
§§
–
215
1.11
(0.39, 3.18)
0.85
*Includes all patients in pediatric analysis cohort with idiopathic PAH (IPAH), familial PAH (FPAH), or pulmonary arterial hypertension (PAH) associated with congenital
heart disease (APAH-CHD; n=199) who have at least 1 day of follow-up from PAH diagnosis (for survival from diagnosis) and enrollment (for survival from enrollment),
and available data for the variable(s) in the model. Cox models from the time of diagnosis adjust for left truncation. All variables were collected both at the time of
diagnosis and enrollment, except for brain natriuretic peptide (BNP) and newly vs previously diagnosed, both of which are included only in the regression model from
enrollment. FPAH and APAH-CHD at enrollment were included in both models; †Estimates are reported for the univariable Cox proportional hazards regression of survival
from the time of PAH diagnosis or enrollment; ‡Reference category for FPAH includes APAH-CHD and IPAH pediatric patients; reference group for APAH-CHD includes
IPAH and FPAH pediatric patients; §Reference category is New York Heart Association/World Health Organization (NYHA/WHO) functional class (FC) I/II; ŒCardiac
index is equal to systemic blood flow (mL/min/m2) for patients with CHD with unrepaired shunts or residual shunts. For all other pediatric patients, it is equal to the Fick
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value if available; otherwise, the thermodilution value is used. #Heart rate and systolic blood pressure (SBP) were measured during right-sided heart catheterization (RHC).
There was not enough heart rate data available for the univariable model to be estimated; **These variables were created at the time of PAH diagnosis if data was available;
otherwise, they were based on data at the time of enrollment; ††The adult definition of acute vasoreactive response is defined as a decrease in mean pulmonary artery
pressure (mPAP) of at least 10 mmHg to an absolute value <40 mmHg, combined with an increase or no change in cardiac output. Too few patients met this criterion to
accurately estimate the hazard over a long period of time. The adapted conventional pediatric definition of an acute vasoreactive response is defined as a decrease in mPAP
of at least 20% and an increase or no change in cardiac index and a decrease or no change in the pulmonary vascular resistance (PVR) to systemic vascular resistance (SVR)
ratio; decreases in cardiac index (if not clinically significant) were permitted if the value remained within normal limits: 2.5–4.0 L/min/m2; ‡‡Presyncope/syncope is a
check-box on the PAH-specific medical history form for initial symptoms later attributed to PAH; §§All variables with P values <0.20 were entered into a stepwise
multivariable Cox proportional hazards regression. The primary multivariable model from the time of PAH diagnosis included only one term: age (HR=1.51 per 5 yrs;
P=0.006). A sensitivity analysis excluding the 17 non-IPAH/FPAH or APAH-CHD patients included both age (HR=1.85, P=0.001) and z-score for height (HR=0.73;
P=0.015). The primary multivariable model from the time of enrollment also included three terms: PVR index (HR=1.15 per 5 Wood units·m2; P<0.001), z-score for weight
(HR=0.71; P=0.005), and FPAH (HR=3.22; P=0.043). A secondary model including marginally significant predictors included five terms: PVR index (HR=1.16 per 5
Wood units·m2; P=0.003), z-score for weight (HR=0.73; P=0.011), FPAH (HR=4.93; P=0.008), BNP <50 pg/mL or N-terminal-proBNP (NT-proBNP) <300 pg/mL
(HR=0.38; P=0.060), and acute vasoreactivity (adapted conventional pediatric definition; HR=0.32; P=0.087). CI, confidence interval; HR, hazard ratio; MAP, mean
arterial pressure; NA, not available.
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Figure Legends:
Figure 1. Five-year survival from diagnostic right heart catheterization (RHC) for all patients
diagnosed with pulmonary arterial hypertension (PAH) during childhood and enrolled in the
Registry to EValuate Early And Long-term PAH disease management (REVEAL) within 5 years
of diagnostic RHC (n=120; 74%±6%. Data points are survival estimates ± standard error at 1, 3,
and 5 years accounting for left truncation.
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Figure 2. Two-year survival from enrollment in the Registry to EValuate Early And Long-term
PAH disease management (REVEAL) for idiopathic/familial PAH (IPAH/FPAH) and
pulmonary arterial hypertension (PAH) associated with congenital heart disease (APAH-CHD).
Two-year survival from enrollment for IPAH/FPAH (90%±3%) and all APAH-CHD (repaired
and unrepaired/partial repair; 85%±4%) was not different; log-rank P value=0.60. Data points
are survival estimates ± standard error at 6, 12, 18, and 24 months.
Figure 3. Two-year survival from enrollment for pulmonary arterial hypertension (PAH)
associated with congenital heart disease (APAH-CHD). Two-year survival from enrollment for
APAH-CHD repaired (86%±7%) and APAH-CHD unrepaired/partial repair (85%±5%) was not
different; log-rank P value=0.77. Data points are survival estimates ± standard error at 6, 12, 18,
and 24 months.
Figure 4. Two-year survival from enrollment for idiopathic PAH (IPAH) and familial PAH
(FPAH). Two-year survival from enrollment for IPAH and FPAH was 92%±3% and 71%±12%,
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respectively; log-rank P value=0.045. Data points are survival estimates ± standard error at 6, 12,
18, and 24 months. PAH, pulmonary arterial hypertension.
Figure 5. Survival within the 5 years from diagnostic right heart catheterization (RHC) for
idiopathic/familial PAH (IPAH/FPAH) and pulmonary arterial hypertension (PAH) associated
with congenital heart disease (APAH-CHD). Five-year survival from diagnostic RHC for
IPAH/FPAH and APAH-CHD was 75%±7% and 71%±13%, respectively; hazard ratio P
value=0.53. Data points are survival estimates ± standard error at 1, 3, and 5 years.
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Survival in Childhood Pulmonary Arterial Hypertension: Insights From the Registry to
Evaluate Early and Long-term PAH Disease Management
Robyn J. Barst, Michael D. McGoon, C. Gregory Elliott, Aimee J. Foreman, Dave P. Miller and D.
Dunbar Ivy
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Circulation. published online November 15, 2011;
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2011 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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http://circ.ahajournals.org/content/early/2011/11/09/CIRCULATIONAHA.111.026591
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