European Heart Journal Advance Access originally published online on June 22, 2006
European Heart Journal 2006 27(14):1737-1742; doi:10.1093/eurheartj/ehl116
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Presentation, survival prospects, and predictors of death in Eisenmenger syndrome: a combined retrospective and case–control study
1 Adult Congenital Heart Centre and Centre for Pulmonary Hypertension, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
2 National Heart and Lung Institute, Imperial College of Science and Medicine, London, UK
3 Department of Paediatric Cardiology and Biomedical Engineering, University Hospital of Schleswig-Holstein, Kiel, Germany
4 Department of Cardiology, Hammersmith Hospital, London, UK
Received 7 December 2005; revised 9 April 2006; accepted 1 June 2006; online publish-ahead-of-print 22 June 2006.
* Corresponding author. Tel: +44 207 351 8602; fax: +44 207 351 8629. E-mail address: m.gatzoulis{at}rbh.nthames.nhs.uk
See page 1644 for the editorial comment on this article (doi:10.1093/eurheartj/ehi823)
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Abstract |
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Aims To characterize contemporary Eisenmenger patients at a large centre for adult congenital heart disease, assess survival prospects, and identify predictors of death in this population.
Methods and results All Eisenmenger patients under follow-up at our centre since 2000 (n=171, mean age 37±12 years) were included. To identify predictors of mortality, a case–control study was performed. Data including symptoms, functional class, medication, laboratory, and electrocardiographic and echocardiographic parameters are presented. Iron deficiency was common and strongly related to phlebotomy (relative risk 4.1, P<0.0001). Haemoglobin concentration was inversely related to arterial oxygen saturations in iron-replete patients (P<0.001) but not in iron-deficient patients. During a median follow-up of 67 months, 20 patients died. Survival at 40, 50, and 60 years of age was 94, 74, and 52%, respectively. When compared with healthy individuals, median survival was reduced by 
20 years in Eisenmenger patients and was worst in those with complex lesions. Predictors of mortality included functional class, signs of heart failure, history of clinical arrhythmia, QRS duration and QTc interval, and low serum albumin and potassium levels.
Conclusion Despite good short-term prognosis, life expectancy is markedly reduced in Eisenmenger patients. Markers of heart failure and parameters associated with arrhythmia are of prognostic value in terms of mortality and may guide clinicians caring for Eisenmenger patients.
Key Words: Eisenmenger syndrome • Congenital heart disease • Pulmonary hypertension • Survival
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Introduction |
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Nearly 50 years ago, Wood1 laid the foundation for our current understanding of the Eisenmenger syndrome as ‘pulmonary hypertension with reversed central shunt’.1,2 Since then, we have experienced quantum leaps in cardiac surgery and paediatric cardiology. Nowadays, Eisenmenger syndrome can be prevented in most paediatric patients. However, when patients do present with established Eisenmenger physiology, treatment options are generally limited to palliative measures and very selected subgroups of patients may be considered for heart–lung transplantation. Recently, however, effective drugs for the treatment of pulmonary hypertension have become available.3–6 These therapies may also be applicable to patients with pulmonary hypertension associated with congenital heart disease, potentially improving symptoms and prognosis. Preliminary results in patients with Eisenmenger physiology are promising.7,8 Thus, risk stratification is increasingly required for the consideration of these costly therapies and for appropriate resource allocation in this patient group.
As annual mortality rates are relatively low in Eisenmenger patients, identification of risk factors is problematic. Although retrospective analyses include a larger number of patients and provide a good overview of the patient characteristics, the limited number of deaths in this population may not allow for an appropriate multivariate analysis and thus different confounders may affect the results. Despite utilizing a smaller number of patients overall, case–control studies include all patients with adverse outcome and may be adjusted for known confounders such as age and underlying diagnosis. Furthermore, increased diagnostic capabilities and improved awareness of congenital heart disease and pulmonary arterial hypertension among professionals may have altered the clinical presentation and may have affected morbidity and mortality of patients with Eisenmenger syndrome when compared with previous reports.9–11
In this study, we aimed to (i) provide a contemporary overview of adult patients with Eisenmenger physiology followed at a single high-volume tertiary centre, (ii) assess survival prospects in this cohort, and (iii) investigate risk factors for mortality.
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Retrospective analysis
This was a retrospective study. We identified all patients with Eisenmenger physiology under regular follow-up at our centre from our computerized database of patients with adult congenital heart disease (operational from 2000). Inclusion criteria were evidence of pulmonary hypertension (confirmed by echocardiography and/or cardiac catheterization) in the presence of a large unrestrictive atrial or ventricular septal defect (VSD) or aorto-pulmonary communication as previously described.1 Patients who had undergone shunt closure previously and those with small restrictive shunts unlikely to be related to pulmonary hypertension were not included. For the retrospective analysis, we included the data of the first full assessment within the study period. In order to minimize inflation of type I error because of multiple comparisons, comparisons among variables were limited to simple but clinically relevant parameters such as age, functional class, and oxygen saturations, which provide a description of the severity of the underlying disease.
Case–control study
Our entire patient population was screened for deaths occurring in Eisenmenger patients between 2000 and 2005. Each patient who died was matched with a surviving control patient of similar age (within 7 years) and underlying anatomy. Medical records were reviewed and underlying characteristics including diagnosis, ECG parameters, echocardiographic findings, and pertinent laboratory results were recorded. For the case–control study, data from the last clinical visit were recorded for mortality cases, whereas for surviving control patients, data around the time of the last clinical visit of the corresponding mortality case (within 6 months) were acquired. Risk factors considered included functional (NYHA) class, deterioration in NYHA class (deterioration of at least one functional class within the last year before the clinical visit), need for more aggressive drug therapy (diuretics and anti-arrhythmic drugs) within the last year before the clinical visit, the presence of clinical signs of heart failure (peripheral oedema or ascites), history of documented clinical arrhythmia, ECG parameters (such as underlying rhythm, QRS duration, QT and QTc interval), laboratory parameters (such as serum electrolytes, creatinine, albumin, liver function tests), cardiac medication, history of pulmonary or systemic emboli, history of pulmonary infections and/or haemoptysis, and history of near-syncope or syncope. In addition, systemic and subpulmonary systolic ventricular function and dimensions were assessed semi-quantitatively from transthoracic echocardiograms by an experienced echocardiographer and quantified as previously described.12 Iron deficiency was defined as a ferritin level 
15 ng/mL or a transferrin saturation 15%. In patients in whom there was discrepancy between these values (n=13), transferrin saturation was considered paramount.
Statistical analysis
Values are presented as mean±standard deviation. Comparisons between groups were made using Student's t-test, the Mann–Whitney U-test, or the 
2 test as appropriate. The Kaplan–Meier survival curves were constructed to illustrate the survival of Eisenmenger patients. Survival prospects were compared with those predicted for an age- and gender-matched healthy cohort of UK residents using life table data (2001–2003 interim life tables) published by the Government Actuary's Department (http://www.gad.gov.uk), as described previously.13
Risk factors for death were identified by a univariate conditional regression analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) for significant predictors were reported. R version 2.1.1. and MedCalc 8.1 (MedCalc Software, Mariakerke, Belgium) were used for statistical analysis. For all analyses, a two-sided P-value of less than 0.05 was considered statistically significant.
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Patient population
Overall, 171 patients (115 females and 56 males) fulfilled inclusion criteria and constituted our study population. The mean age at the last visit was 37±12 years (range 14–72 years). Ninety-seven patients (57%) had simple anatomy (12 atrial septal defect, 63 VSD, and 22 patent arterial duct), whereas 74 patients (44%) had complex anatomy, comprising atrioventricular septal defects, ‘univentricular heart’, transposition of the great arteries, and common arterial trunk. There were 48 patients with Down's syndrome (28%). Down patients were significantly younger when compared with the remaining patients (30±9 vs. 40±12 years, P<0.001). The majority of the patients was symptomatic (94%), whereas only 6% of patients reported no symptoms. Classifying symptoms according to the NYHA classification revealed that 6% of patients were in functional class I, 48% in class II, 42% in class III, and only 4% in class IV. When patients were stratified according to the location of shunting, no significant difference in symptoms could be found: symptoms corresponding to NYHA class III or above were found in 54% of patients with atrial shunt, 54% of patients with a shunt at ventricular level, and 57% of patients with aorto-pulmonary shunt (P=0.96).
Mean oxygen saturation in room air was 84±8% and was lower in patients with higher NYHA class (81±7% in patients with NYHA class III or IV vs. 86±8 in patients with NYHA class I or II, P<0.001) and in those with complex anatomy (82±8% in patients with complex lesions vs. 85±8% in patients with simple lesions, P=0.006).
The majority of patients was in sinus rhythm (98%) at the last visit, whereas only 2% of patients were in atrial fibrillation (n=2) or had a pacemaker rhythm (n=2, for complete heart block). A clinical history of arrhythmia requiring cardioversion or anti-arrhythmic therapy was documented in a minority of patients (13%). Palpitations, however, were more common and were present in 44 patients (26%). Furthermore, 23 patients (13%) experienced at least one syncopal episode during the follow-up period.
Dizziness was reported in 25 patients (15%) and was related to history of syncope, independent of age and survival status (P<0.001). Thirty-five patients had a history of haemoptysis. Patients with haemoptysis were more likely to be anti-coagulated with warfarin (P=0.04). In addition, patients in a higher functional class were more likely to have clinical signs of heart failure, independent of age and survival status (P=0.003).
Medication
Twenty-three patients were treated with a beta-blocker, 19 patients with an angiotensin-converting enzyme (ACE)-inhibitor, seven with a calcium antagonist, and 17 patients with digoxin. Forty-six patients received diuretics. Twenty patients were treated with potassium-sparing diuretics such as spironolactone or amiloride. Only one patient (with the lowest potassium level) was treated in our hospital with potassium supplements. Forty-nine patients were anti-coagulated with warfarin, whereas 17 patients were treated with anti-arrhythmic drugs. In addition, 39 patients had home oxygen therapy and 20 patients were treated with advanced therapies for pulmonary hypertension (18 with bosentan—an endothelin antagonist, one patient with sildenafil—a phosphodiesterase-5-inhibitor, and one with a combination of both).
Laboratory measures, haematology, and iron deficiency
Laboratory results were available in 129 patients. Mean potassium level was 4.3±0.5 mmol/L (range 3.1–5.7 mmol/L). Mean haemoglobin concentration was 19.2±3.2 g/dL (range 10.1–26.1 g/dL). Iron deficiency was found in 24 patients. Twenty-nine patients had a history of phlebotomy. Phlebotomy was strongly associated with the presence of iron deficiency (relative risk 4.1, 95% CI 2.2–7.7, P<0.0001). There was an inverse relationship between resting oxygen saturations and haemoglobin levels in patients without iron deficiency, as shown in Figure 1. However, no such relationship could be found in patients with iron deficiency.
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Survival analysis
During a median follow-up period of 67 months (range 8–68), 20 patients died. Nine patients died because of progressive heart failure (45%), whereas 11 patients (55%) died unexpectedly, presumably suddenly. These numbers are comparable with those reported by Niwa et al.,14 in which 63% of patients died suddenly. Survival at 30, 40, 50, and 60 years of age was 98, 94, 74, and 52%, respectively (Figure 2). Patients with complex anatomy had a significantly worse prognosis when compared with those with simple anatomy (P=0.02). Although 50% of patients with simple anatomy were still alive at 58 years, 50% of those with complex anatomy had died at the age of 42, as demonstrated in Figure 3. In addition, this figure also shows the estimated survival curve for a gender-matched cohort of healthy individuals on the basis of the life tables for UK and Wales (2001–2003) published by the Government Actuary's Department. Survival was significantly worse for Eisenmenger patients than expected for a matched healthy cohort (standardized mortality ratio 3.8, 95% CI 2.0–7.0, P<0.0001). Although 20 Eisenmenger patients died during follow-up, the expected mortality in the matched population was only 5.3.
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Predicted survival is based on the life tables for UK and Wales (2001–2003 interim life tables) published by the Government Actuary's Department.Predictors of mortality
Twenty patients died (eight males) and were included in the case–control study. Underlying cardiac anatomy was a non-restrictive VSD in five patients, atrial septal defect in four, common arterial trunk in four, transposition of great arteries with VSD in three, and patent arterial duct in four. Mean age at death was 43.2±10.5 years.
On conditional logistic regression analysis, functional (NYHA) class (OR=3.37, 95% CI 1.05–10.8, P=0.041) and the presence of signs of heart failure (OR=9.00, 95% CI 1.14–71.04, P=0.037) were found to be predictive of death. On ECG, longer QRS duration (OR=1.10/ms, 95% CI 1.002–1.199/ms, P=0.044) and longer QTc interval (OR=1.07, 95% CI 1.001–1.151/ms, P=0.047) were associated with a worse outcome. Low serum albumin (OR=0.84 g/L, 95% CI 0.71–0.99 g/L, P=0.034) and low potassium levels (OR=0.06 mmol/L, 95% CI 0.004–0.960 mmol/L, P=0.047) were also predictive of death.
In addition, a history of clinical arrhythmia (OR=9.00, 95% CI 1.14–71.03, P=0.037), deteriorating NYHA class (OR=11.00, 95% CI 1.42–85.20, P=0.022), and need for more aggressive drug therapy (OR=9.00, 95% CI 1.14–71.03, P=0.037) within 1 year before the last clinic visit were all predictive of poor outcome.
In contrast, neither medication nor semi-quantitative echocardiographic assessment of right and left ventricular size and function was predictive of death. Furthermore, previous history of pulmonary or systemic emboli, recurrent pulmonary infections or haemoptysis, and near-syncope or syncope were not significantly different between the two outcome groups.
Discussion
The current study characterizes the population of Eisenmenger patients at a large tertiary centre caring for adults with congenital heart disease and identifies predictors of death in this population. Our major findings are: Iron deficiency is relatively common in Eisenmenger patients and is related to phlebotomy. Unlike iron-replete patients, iron-deficient patients seem to lose their ability to adapt haemoglobin concentrations to low arterial oxygen saturations in order to maintain blood oxygen carrying capacity; despite a relatively good short-term prognosis, median survival is reduced by 20 years in patients with simple underlying anatomy and a further 20 years in those with complex lesions. Low functional (NYHA) class, clinical signs of heart failure, and a history of clinical arrhythmia predict poor outcome. In addition, recent change in functional class and the need for increased anti-arrhythmic and diuretic therapies were related to poor outcome. Laboratory and ECG-related parameters associated with chronic heart failure and arrhythmia (low serum albumin, low potassium levels, and longer QRS duration and QTc interval) were also predictive of mortality.
Limited information on characteristics and prognostic variables are available for contemporary Eisenmenger patients. Cantor et al.10 reported predictors of death in Eisenmenger patients referred for lung transplantation, whereas Daliento et al.11 characterized 188 Eisenmenger patients followed-up at three different European centres over three decades. The current report expands on these studies in several aspects: (i) all patients were followed at a single centre, thereby avoiding differing management strategies at different centres; (ii) only contemporary patients were included, reflecting current practice; and (iii) to the best of our knowledge, this is the first case–control study in this population.
Clinical presentation
The vast majority of Eisenmenger patients included in the current study was found to be symptomatic and almost half of the patients reported severe limitations (NYHA class III or higher). A higher functional class was related to lower resting arterial oxygen saturations and a higher incidence of ascites or peripheral oedema. In contrast to previous reports,1 we did not confirm an association between the location of shunting and the degree of physical limitation. A minority of patients (10%) was on medical therapy with beta-blockers, ACE-inhibitors, or calcium antagonists. This is likely to reflect the lack of evidence for a beneficial effect of these therapies in this cohort as well as the apprehension that these drugs may induce systemic vasodilation with a subsequent increase in right-to-left shunt. Nineteen patients were treated with advanced therapies for pulmonary hypertension (endothelin receptor or phosphodiesterase-5 antagonists) as part of ongoing clinical trials at our centre or on a compassionate basis. Twenty-three per cent of patients were treated with oxygen at home. Although the data regarding the chronic use of oxygen in patients with Eisenmenger syndrome are conflicting,15,16 we would still use oxygen on an ad hoc basis in selected patients.
Haemoptysis was reported in 20% of patients in the current study. This is consistent with the previously reported incidence rates, ranging between 11 and 33%.1,10,11 Haemoptysis was not related to low haemoglobin concentrations or an increased risk of death, in accordance with the study by Daliento et al.11 In the current study, an association between haemoptysis and anti-coagulation therapy was present. However, some patients are anti-coagulated for pulmonary arterial thrombosis, which in itself is often associated with haemoptysis because of pulmonary infarction.1,17 Therefore, the relationship between anti-coagulation and haemoptysis may be confounded in this population.
Haematology and iron deficiency
The vast majority of Eisenmenger patients had secondary erythrocytosis as reflected by elevated mean haemoglobin concentrations when compared with reference values. This represents an adaptation to reduced oxygen carrying capacity due to right-to-left shunting, as reflected in low arterial oxygen saturations. In the present study, we found a strong correlation between arterial oxygen saturations and haemoglobin values. However, it deserves emphasis that this association held true only in iron-replete patients, suggesting that iron-deficient patients were unable to increase their haemoglobin concentrations in proportion to reduced arterial oxygen saturations in order to maintain their oxygen carrying capacity of the blood (Figure 1). The treatment of Eisenmenger patients included in the current study represents a joint effort between our centre and referring physicians from secondary care. We operate a policy of discouraging routine phlebotomy in patients with Eisenmenger syndrome because of well-recognized complications such as iron-deficient anaemia and increased risk for cerebrovascular accidents.18 In addition, it appears that a significant proportion of patients are iron-deficient, even though they may have a normal iron intake and without being subjected to routine venesections. In our practice, iron deficiency once identified is an important therapeutic target.
Survival and predictors of death
This study demonstrates that, compared with the general population, life expectancy in contemporary patients with Eisenmenger physiology is reduced by 20 years and the mortality risk is increased 3.8-fold. Despite this, short-term mortality is relatively low (12.5% at 5 years). This finding is consistent with previous studies,10,11 supporting the concept that survival prospects in Eisenmenger patients are better than previously appreciated and are far superior to those observed in patients with primary pulmonary hypertension.9 Survival prospects were significantly poorer in patients with complex anatomy when compared with those with simple underlying cardiac lesions. Although 50% of patients with simple anatomy were still alive at the age of 58, 50% of those with complex anatomy had died at the age of 42. Only three out of 48 patients with Down's syndrome died during follow-up, precluding a meaningful comparison between survival prospect of patients with and without Down's syndrome. The relatively low mortality in Down patients observed may be related to the fact that Down patients in the current study were significantly younger than the remaining population.
We found that signs and symptoms of heart failure (functional class and the presence of oedema) predict death in Eisenmenger patients. Consistent with these findings, laboratory parameters related to impaired liver function were also predictive of mortality and may be secondary to congestive ventricular failure in this setting. In addition, a history of clinical arrhythmia was predictive of death. Low potassium concentrations, potentially associated with a greater risk of malignant tachy-arrhythmias, also carried prognostic information. The prognostic value of functional class is consistent with previous reports.10,11 In contrast, discrepant data on the predictive value of arrhythmias exist: one previous study found a history of arrhythmia to be predictive of mortality,10 another report could not identify an association between arrhythmia and death.11 This needs to be seen within the limitations of retrospective reports. None of these previous studies describes an association between the signs of heart failure and risk of death. In accordance with the data published by Cantor et al.10 and Daliento et al.,11 our data suggest that a history of syncope is not related to poor outcome in Eisenmenger patients. Earlier studies found syncope to be an indicator of poor outcome.1,19 Furthermore, our data could not confirm the predictive value of ECG-derived voltage criteria for right ventricular hypertrophy as reported previously.10 This, however, does not invalidate the published results, and indeed, we found different ECG parameters (QRS duration and QTc) to be predictive of poor outcome in our population. Further prospective studies are, therefore, required to validate these ECG markers and their predictive value in Eisenmenger patients.
Limitations of the study
The population of patients employed in this study reflects the clinical workload of a tertiary adult congenital heart disease centre. Hence, we cannot exclude the possibility that survival prospects are overestimated by the current study. Patients with severe underlying lesions and very limited life expectancy may have deceased early in life and were, therefore, not seen in our adult congenital service. In contrast, referral to a tertiary centre is often dictated by symptoms and disease progression. Therefore, our study could as well be underestimating the survival prospects of patients with Eisenmenger physiology. Further studies including patients who are currently not attending tertiary centres could provide additional information.
This study was not designed to examine the precise mode of death in this cohort. Indeed, necropsy data were available only in a small minority. We cannot exclude the possibility that multiple comparisons employed in the retrospective analysis and case–control study lead to an increase in experimental type I error.
Echocardiographic ventricular function was assessed semi-quantitatively and refers to systolic ventricular function, whereas diastolic function was not assessed in the current study. Further imaging with cardiac magnetic resonance also providing robust information on pulmonary vascular bed may shed additional light on late pathophysiology and prognostication.
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Conclusion |
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There is a four-fold increase in mortality among contemporary adult patients with Eisenmenger syndrome followed-up in a tertiary specialized centre. Poor functional class, clinical and laboratory signs of heart failure, and a history of arrhythmias were all predictive of death. These data may be helpful in guiding clinicians and assisting targeting therapies in patients with Eisenmenger physiology.
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Acknowledgements |
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We thank Mr Tom Lucas and Ms Leslie Jones for their undivided support to the pulmonary arterial hypertension service. G.-P.D. was supported in part by an educational grant from Actelion, UK. M.A.G. and the Royal Brompton Adult Congenital Heart Centre have received support from the British Heart Foundation. K.D. received support from the European Society of Cardiology.
Conflict of interest: none declared.
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