Belgian Eisenmenger registry
The Belgian Eisenmenger registry: Implications for treatment strategies?
Alexander Van De Bruaene MD, Marion Delcroix, MD, PhD°, Agnes Pasquet, MD, PhD*,
Julie De Backer MD, PhD**, Michel De Pauw, MD**, Robert Naeije MD, PhD***, Jean-Luc
Vachiéry***, Bernard Paelinck, MD, PhD$, Marielle Morissens, MD$$, Werner Budts MD,
PhD.
Division of Cardiology and Pneumology°, University Hospitals Leuven, *University
Hospitals St Luc Brussels, **Ghent University Hospital, ***Erasme University Hospital
Brussels, $University Hospital Antwerp, Belgium, and $$CHU Brugman Brussels.
Address for correspondence:
Werner Budts, MD, PhD
Congenital and Structural Cardiology
University Hospitals Leuven
Herestraat 49
B-3000 Leuven
Tel: 00-32-16-344369
Fax: 00-32-16-344240
E-mail: werner.budts@uz.kuleuven.ac.be
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Belgian Eisenmenger registry
Abstract
Objective: Pulmonary arterial hypertension (PAH) associated with congenital heart disease
(CHD) usually results from a systemic-to-pulmonary shunt. Eisenmenger syndrome (ES) is
characterised by severe irreversible PAH and reversal of a previous systemic-to-pulmonary
shunt. A national registry of ES patients was initiated to optimise patient care and to provide
epidemiological information regarding PAH and CHD in Belgium.
Methods: All ES patients, older than 18 years, were selected through the local databases of ten
centres in Belgium. After written informed consent, demographic, clinical, biochemical,
technical, and treatment data were entered into the web based registry.
Results: Ninety-one patients were included in the registry. Mean age was 3611 years (range
18-59 years). Complete atrioventricular septal defect (N=26, 28.6%), followed by ventricular
septal defect (N=25, 27.5%) were the commonest defects. Forty-five percent were patients
with Down syndrome. Down patients were younger (329 versus 4012 years; P=0.039), had
worse functional capacity (Class II/III ratio: 15/16 versus 21/8; P=0.035) and received
significantly less specific PAH treatment (7% versus 38%; P=0.002).
Conclusion: Through the national Eisenmenger registry, 91 adult patients with ES were
identified (estimated prevalence 11 per million inhabitants). Almost half of them were Down
patients. Although having worse functional capacity, significantly less Down patients were
receiving specific PAH treatment.
Keywords
Congenital heart disease, down syndrome, epidemiology, eisenmenger syndrome, pulmonary
hypertension, registry.
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Belgian Eisenmenger registry
Introduction
Adult patients with CHD represent a relatively new and continuously growing population.
Currently, up to 90% of patients with congenital heart defects reach adulthood thanks to
advances in medical, interventional and surgical procedures. PAH, defined as a mean
pulmonary arterial pressure of > 25mmHg at rest or > 30 mmHg on exercise, develops in
about 10% of patients with congenital shunts, whereas some of them evolve to the extreme
end of the spectrum, the ES. [1,2]
In Belgium, a few tertiary care centres developed advanced adult CHD clinics over the last
years and the number of patients treated in each centre is continuously growing. Additionally,
a number of “stable” patients are followed in secondary care centres. So far, there is no
structured database of patients with CHD in Belgium and hence, it is currently difficult to
identify and track adults with CHD in Belgium.
Several reports stressed the importance of the implementation of national registries to provide
epidemiological information on CHD and PAH and to optimise patient care by developing an
efficient organisational structure, evidence based treatment protocols, and by assessing
research and new treatment modalities.[3,4] Examples of recently developed databases are the
CONCOR (‘CONgenital CORvitia’) project, a national registry and DNA-bank of patients
with CHD in the Netherlands[5] and the EUROHEART survey on adult CHD, a retrospective,
multi-centre study describing a European cohort of adults with CHD.[6] Two recently
published PAH registries underline the need for further epidemiological research regarding
PAH associated with CHD, because of a probable underestimation of the prevalence of PAH
associated with CHD.[7,8]
To obtain more structured national data and to create a forum for inter-academic and interdisciplinary cooperation regarding adult CHD and PAH in Belgium, a national registry of
3
Belgian Eisenmenger registry
Eisenmenger patients was initiated. Here, we want to report the baseline characteristics of the
patients included in this registry and draw the first conclusions.
4
Belgian Eisenmenger registry
Methods
Patient selection
All patients with Eisenmenger physiology, older than 18 years, and living in Belgium, were
eligible candidates for inclusion in the national registry. Eisenmenger physiology was defined
as an intracardiac systemic-to-pulmonary communication with a reversal of the left-to-right
shunt, resulting from severe pulmonary hypertension. Patients either had cyanosis at rest or
during exercise. The Ethics Committees of the participating centres agreed with the registry,
but before inclusion in the database, each patient, or his/her tutor, had to sign an informed
consent. We aimed to include all adult patients with ES. Except age, no exclusion criteria
were present.
Participants and organisation
The Eisenmenger registry was initiated in 2005 by the Belgian task force for pulmonary
hypertension in collaboration with ten university and/or academic hospitals (Appendix).
Belgium is a small country where the health care system allows easy access to tertiary care
centres so that we might assume that nearly all patients with CHD and ES in Belgium were
included. The task force was responsible for the creation, implementation, and management of
the Eisenmenger registry.
The registry was developed and is currently maintained by an independent data manager
(Alabus Ag, Switzerland). The validity of a similarly designed data base was already proven
in Switzerland and Austria. The input of data is web-based, so that each participating centre
could log into the registry through internet with a personalized password. Actelion
Pharmaceuticals Ltd (Allschwil, Switzerland) provided financial support to cover the costs of
the development and the maintenance of the database, but had no access to the data entered.
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Belgian Eisenmenger registry
Data collection
After signing the informed consent, data could be registered under a unique code for each
patient. Physicians were only able to look at data from patients who were entered by
themselves. Demographic data, medical history (Down syndrome or not, surgical procedures,
and non cardiac history), clinical baseline characteristics (functional status), technical
investigations (ECG, RX thorax,…), biochemical data, and treatment were collected. After
registration, follow-up data could be entered.
Statistical analysis
All continuous variables were tested for normality. If present, mean ± standard deviation (SD)
were used. Proportions were described with numbers (n) and percentages (%).
For differences between continuous variables with normal distribution, an unpaired t-test was
performed. Proportions were compared with the Chi square test. All tests were two-sided and
P < 0.05 was considered to be statistically significant. Tests were performed with SPSS for
Windows (version 15.0). Prevalence of ES was calculated as the ratio of all patients included
in the registry and the total (adult) population (Belgium 2008: ~8.4 million).
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Belgian Eisenmenger registry
Results
Patient characteristics
Most patients with the ES were identified through the databases of the participating centres.
More than 90% of them (or their tutor) agreed with inclusion in the registry and signed
informed consent. A total of 91 patients were included, 69% (N=63) were female. Mean age
was 3611 years (range 18-59 years). The main underlying diagnosis was complete
atrioventricular septal defect (AVSD) (N=26, 28.6%) followed by ventricular septal defect
(VSD) (N=25, 27.5%), complex defects (N=22, 24.2%), atrial septal defect (ASD) (N=10,
11%), and persistent arterial duct (PDA) (N=8, 8.8%). Forty-five percent (N=41) of the
patients had Down syndrome.
The functional class of the patients at inclusion is illustrated in Table 1. Reported symptoms
were infrequent: palpitations (1%), vertigo (1%), syncope (4%), headache (8%), limb oedema
(4%), chest pain (4%), haemoptysis (14%), epistaxis (1%). Clinical parameters are provided
in table 2 and relevant biochemical characteristics are summarized in Table 3. Twenty-three
percent of the patients were treated with specific PAH therapy (Table 4).
Prevalence of ES in Belgium
The overall population prevalence in the adult population of Belgium (~8.4 million) of ES
was 11 per million population.
Down versus non-Down patients
Down patients were younger than non-Down patients (329 versus 4012 years; P = 0.039).
As expected, Down patients were smaller than non-Down patients (15110 cm vs. 1648 cm;
P < 0.001), but had a similar weight (6112 kg vs. 6111 kg; P = 0.796), resulting in a higher
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Belgian Eisenmenger registry
BMI in the Down syndrome group (265.4 kg/m² vs. 224.1 kg/m²; P = 0.005). An overview
of these comparisons and other clinical parameters is listed in Table 2.
VSD (N=14, 28 %) and complex defects (N=19, 38%) were the most common defects in the
non-Down syndrome group, whereas in Down patients the AVSD was most prevalent (N=26,
63.4%). Although patients with Down syndrome had worse functional capacity when
compared to the non-Down patients (Class II/III ratio: 15/16 versus 21/8; P = 0.035), only
three Down patients (7%) received specific PAH treatment, which was significantly lower
than the non-Down patients (38%) (P = 0.002) (Table 4).
Finally, differences in biochemical parameters between both groups are listed in Table 3.
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Belgian Eisenmenger registry
Discussion
Ninety-one patients with the typical ES were identified through the national Eisenmenger
registry in Belgium, a prevalence of 11 per million adults older than 18 years. Almost half of
them had Down syndrome. Most non-Down patients were receiving specific PAH treatment
according to their functional class, whereas most Down-patients in class III did not.
ES is defined as severe PAH associated with a large and non-restrictive intra- or extracardiac
shunt, which leads to flow reversal through the shunt and central cyanosis.[2,9] As stated in
the updated Venice classification[10], there are differences in pathological and
pathophysiological aspects among patients with PAH associated with CHD, which are
important for diagnosis, treatment and prognosis.[11] Some congenital heart defects with
functional systemic-to-pulmonary shunts, such as an unrestricted AVSD, VSD, or a large
PDA, invariably lead to pulmonary vascular remodelling and the clinical syndrome of PAH.
By contrast, pre-tricuspid systemic-to-pulmonary shunts, as in the ASD, will only evolve to
PAH in 10-20% of the cases.[9,12]
Indeed, in general, it has been estimated that about 10% of patients with congenital shunts
might develop PAH, whereas some of them evolve to the extreme end of the PAH spectrum,
the ES.[1,2] Fortunately, due to better diagnostic tools and earlier defect repair, the evolution
to ES in CHD has declined from ± 8% in the 1950’s to about 1-2% today.[1,2,13]
However, epidemiological data regarding PAH associated with CHD remains scarce, often
sub-represented in PAH registries, emphasising the need for further epidemiological research.
Of the 1877 patients included in the Euro Heart Survey on adult CHD, which reflects a more
selected population of patients treated at referral centres, 531 patients suffered from PAH
(28,3%) and 231 patients (12,3%) had the typical ES.[14] In the Dutch CONCOR database, of
the 5970 patients registered, 248 (4.2%) patients were characterized by PAH and 65 (1.0%)
had evolved to the typical ES.[1] Using Dutch demographic data (2007), an estimated
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Belgian Eisenmenger registry
prevalence of 5.24 adult patients with ES per million is acquired. In PAH registries, the
relative proportion of patients with PAH and CHD is also quite variable. The French Network
on PAH (674 patients included in 2002-2003) and the Scottish Pulmonary Vascular Unit (374
patients hospitalised between 1986-2001) reported a proportion of 11% (N=76) and 23-27%
(N=88), respectively.[7,8] Taken together, these results suggest a prevalence of patients with
PAH associated with CHD in Western countries between 1.6 and 12.5 cases per million
adults, with 25-50% having ES.[11]
Most registries have the limitation of an important selection bias. Nevertheless, we suggest
that the number of 91 patients is rather representative to estimate the prevalence of adult
patients with ES in Belgium (11 per million inhabitants), which is twice the prevalence
suggested by the CONCOR database.
Despite comparable morbidity, survival prospects for Eisenmenger patients are far superior
compared with idiopathic PAH.[15] It has been suggested that the presence of a ‘fetal’
phenotype of the right ventricle and/or the presence of a shunt, allowing right-to-left shunting
when pulmonary pressure increases, are responsible for the prolonged survival in ES patients.
[16,17] Interestingly, progressive histological changes have initially and exclusively been
described in patients with PAH associated with CHD[18], which makes this subcategory of
PAH patients particularly interesting. As these histological pulmonary vascular changes are
similar to other forms of PAH, disease-targeting therapy which addresses the prostacyclin axis
(prostanoids), NO/cGMP axis (phosphodiesterase (PDE) inhibitors) or endothelin axis
(endothelin receptor antagonists (ERA)), has also been tried as treatment for patients with ES
with similar results.[19] The placebo-controlled BREATHE-5 trial showed in ES with WHO
class III that a dual-ERA (bosentan) significantly improved pulmonary hemodynamics and
exercise capacity.[20] Improvement of functional class, exercise tolerance, and pulmonary
hemodynamics, was also found in several uncontrolled studies treating patients with PDE
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Belgian Eisenmenger registry
inhibitors (sildenafil) or prostacyclin analogues. [10,21] According to the current guidelines,
most of our registered patients were receiving specific PAH treatment, except the Down
patients.
Indeed, an important proportion of patients included in the registry (45%) had Down
syndrome. This number is higher than reported by others.[15,22,23] This might be explained
by three reasons. First, congenital heart defects are more prevalent in patients with Down
syndrome, which has been estimated between 30% and 50%.[24] Among these, AVSD was
the most common defect (35 – 60%), followed by VSD (15 -35%).[24] Both defects, when
not repaired, might lead early to the development of PAH. Second, Down patients seem to be
more prone to develop PAH, showing a more severe form of pulmonary vascular disease at an
earlier stage of life.[25,26] And finally, earlier there has been some controversy regarding the
surgical policy of congenital heart defects in Down patients, where some authors questioned
the advisability of repairing complete AVSD in patients with DS, on the assumption that early
surgery carries a high risk for an uncertain prospect.[27] This conservative approach resulted
in several un-repaired defects, which could evolve to PAH. However, since several authors
suggested that the presence of Down syndrome would be no risk factor for surgical shunt
repair[28,29], more Down patients’ congenital heart defects have been corrected. This will
probably lead to a decrease in prevalence of ES in the near future. Nevertheless, co-morbidity
remains not uncommon, so that accurate risk assessment before surgical interventions is
always necessary.
We also found that a significantly smaller proportion of Down patients received specific PAH
treatment, although they were younger, had lower functional capacity, higher hematocrit
levels and a more impaired renal function, all of which are determinants of poorer
outcome.[15,22,23] There are several reasons why Down patients received less specific PAH
treatment. First, there is the issue of evidence based medicine. Until today, no randomized
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Belgian Eisenmenger registry
controlled trials have been performed to evaluate the benefit of specific PAH treatment in
Down patients. Recent studies, including the BREATHE-5, applied rather strict inclusion
criteria for their study populations, frequently excluding patients with Down syndrome or
with complex congenital heart defects.[20] However, a recent study reported that bosentan
administration was safe and well tolerated and led in the first months of treatment to a similar
improvement in exercise tolerance as observed in non-Down patients.[30] Anyhow, bosentan
has recently been approved by the EMEA (European Medicines Agency) for treatment of ES
(including patients with Down syndrome) and it is expected that more Down patients with ES
will receive specific PAH treatment in the future. Second, in Belgium a right heart
catheterization is required for the reimbursement of chronic treatment with PAH medication.
For most Down patients, this requires general anaesthesia. Although feasible, this implies
additional risk and a lot of patients drop out at this point.
The registry and the data obtained from the registry have some shortcomings. First, for
inclusion in the Eisenmenger registry an informed consent was required. Although more than
90% of patients (or their tutor) agreed to participate in the study, a selection bias of the
patients might be present. The contribution of the different centres to the registry might differ,
adding to this selection bias. Second, not all centres used the follow-up protocol as predefined
in the registry, so that some data could be missing. Data such as 6 minute walk test,
echocardiography, neurohormones and hemodynamic data haven’t been included in the
registry yet. However, by proposing a general protocol, participating centres will start to use
it, which will allow to have a more complete data set for future outcome analysis. Third,
reasons for the higher percentage of Down patients with ES and the lower percentage of
patients treated with specific PAH treatment given in the text are speculative as the registry
provides no information on the reasons why patients have or haven’t been operated on or been
treated with specific PAH treatment.
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Belgian Eisenmenger registry
Conclusion
In conclusion, through the national Eisenmenger registry, a substantial number of patients
with ES were identified, which allows a realistic prevalence estimate of 11 adult patients with
ES per million in Belgium, which is higher than reported in other registries. Although most
patients were receiving specific PAH treatment according to their functional class, most
Down patients were not. Whether or not to treat Down patients with specific PAH treatment
remains an important dilemma in the current clinical management.
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Belgian Eisenmenger registry
Acknowledgements
We want to thank Actelion Benelux, who gave the investigators the logistical support to start
with a national registry of Eisenmenger patients. Actelion Benelux also supported financially
the development and maintenance of registry, which was done by Alabus Ag (Switzerland).
We want to thank Leuven Coordinating Centre to help us with data input.
Conflicts of interest
None declared.
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Belgian Eisenmenger registry
Appendix : Participating centres and investigators
Prof. Dr. Werner Budts UZ Leuven, Prof. Dr. Marion Delcroix UZ Leuven, Prof. Dr. Agnes
Pasquet Clin. Univ. Saint Luc, Prof. Dr Joelle Kefer Clin. Univ. Saint Luc, Dr. Julie De
Backer UZ Gent, Prof. Dr. Daniel De Wolf UZ Gent, Dr. Michel De Pauw UZ Gent, Prof. Dr.
Robert Naeijé Hopital Erasme, Prof. Dr. P Evrard, Clin. Univ. Mnt Godinne, Dr. Mark
Meysman UZ Jette, Dr. Marielle Morissens CHU Brugman, Prof. Dr. Luc Pierard CHU Sart
Tilman, Dr. Marco Naldi CHU Sart Tilman, Dr. Thierry Weber Hopital de la Citadelle, Prof.
Dr. L. Delaunois Clin. Univ. Mnt Godinne, Dr. Hans Slabbynck AZ Middelheim, Dr. Dirk
Van Ranst UZ Antwerpen, Prof Dr. Bernard Paelinck UZ Antwerpen, Prof. Dr. Walter Van
Mieghem ZOL.
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Belgian Eisenmenger registry
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Tables
Table 1: Functional classes of the Eisenmenger patients at inclusion. (percentage of patients)
Global Population
Down syndrome
Non-Down syndrome
NYHA I
10%
0%
10%
NYHA II
44%
21%
23%
NYHA III
41%
30%
11%
NYHA IV
4%
0%
4%
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Belgian Eisenmenger registry
Table 2. Demographic and clinical characteristics
P-value
Global
Down
Non-Down
Down vs
Population
syndrome
syndrome
non-Down
Female/male (n)
63/28
24/17
39/17
0.045
Age (y)
36±11
32±9
40±12
0.039
Length (cm)
158±11
151±10
164±8
< 0.001
Weight (kg)
60±11
61±12
61±11
0.796
BMI
24±5
26±5
22±4
0.005
Systolic BP (mmHg)
118±20
108±11
125±22
< 0.001
Diastolic BP (mmHg)
72±12
65±7
78±12
< 0.001
Heart rate (beats/min)
77±16
72±11
83±19
0.037
Oxygen saturation (%)
84±8
84±6
84±9
0.937
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Belgian Eisenmenger registry
Table 3. Biochemical characteristics
P-value
Global
Down
Non-Down
Down vs
Population
syndrome
syndrome
non-Down
Haematocrit (%)
56.9±9.4
60.4±5.7
51.4±11.6
< 0.001
Hemoglobin (g/dl)
19.0±3.4
20.1±1.9
17.3±3.9
0.001
MCV (fl)
94.9±6.7
95.9±8.1
91.0±11.6
0.060
Creatinine (g/dl)
1.1±0.4
1.2±0,4
1.1±0.5
0.523
Uric acid (mg/dl)
6.9±2.4
7.4±2.5
6.0±2.0
0.029
Iron (mg/dl)
113.3±67.6
115.0±62.2
105.4±64.1
0.701
TSH (mIU/l)
4.5±3.9
6.2±5.2
3.2±1.8
0.054
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Belgian Eisenmenger registry
Table 4. Type of specific treatment of patients with Eisenmenger syndrome
P-value
Specific
Global
Down
Non-Down
Down vs non-
Population
syndrome
syndrome
Down
22 (23%)*
3 (7%)
19 (38%)
69 (77%)
38 (93%)
31 (62%)
treatment
No specific
treatment
* specific treatment: alpha-blocking agent (1%), bosentan (10%), sitaxsentan (8%), sildenafil
(2%), remodulin (1%), sildenafil + bosentan (1%)
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