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A binational registry of adults with pulmonary arterial hypertension complicating congenital heart disease G. Strange,1,2,3 M. Rose,4 F. Kermeen,5 C. O’Donnell,6 A. Keogh,7 E. Kotlyar,7 L. Grigg,8 A. Bullock,9 P. Disney,10 N. Dwyer,11 H. Whitford,12 D. Tanous,13 C. Frampton,14 R. Weintraub3,4 and D. S. Celermajer15 1
Department of Medicine, University of Notre Dame and 9Department of Paediatric Cardiology, Royal Perth Hospital, Perth, Western Australia, Pulmonary Hypertensions Society ANZ Inc., 7Department of Cardiology, St Vincent’s Hospital, 13Department of Cardiology, Westmead Hospital, 15 Sydney Medical School, Sydney, New South Wales, 3Murdoch Children’s Research Institute, 4Department of Cardiology, Royal Children’s Hospital, 8 Department of Cardiology, Royal Melbourne Hospital, 12Department of Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria, 5Department of Respiratory Medicine, The Prince Charles Hospital, Brisbane, Queensland, 10The Royal Adelaide Hospital, Adelaide, South Australia and 11 Department of Cardiology, Royal Hobart Hospital, Hobart, Tasmania, Australia; 6Department of Cardiology, Auckland City Hospital, Auckland and 2
14
Department of Cardiology, University of Otago, Christchurch, New Zealand
Key words pulmonary arterial hypertension, PAH, congenital heart disease. Correspondence David S. Celermajer, Cardiology Department, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. Email: [email protected] Received 15 March 2015; accepted 20 May 2015. doi:10.1111/imj.12821
Abstract Background: The management of children with congenital heart disease (CHD) has improved over recent decades and several patients surviving with CHD into adulthood are increasing. In developed countries, there are now as many adults as there are children living with CHD. Pulmonary arterial hypertension (PAH) occurs in ∼5% of patients with CHD. Aim: We aimed to understand the characteristics and outcomes of this emerging population. Methods: We collected data retrospectively and prospectively from 12 contributing centres across Australia and New Zealand (2010–2013). Patients were included if they had been diagnosed with PAH and CHD and had been seen once in an adult centre after 1 January 2000. Results: Of 360 patients with CHD-PAH, 60% were female and 90% were New York Heart Association functional class II or III at the time of adult diagnosis of PAH. Mean age at diagnosis of PAH in adulthood was 31.2 ± 14 years, and on average, patients were diagnosed with PAH 6 years after symptom onset. All-cause mortality was 12% at 5 years, 21% at 10 years and 31% at 15 years. One hundred and six patients (30%) experienced 247 hospitalisations during 2936 patient years of follow up. Eighty-nine per cent of patients were prescribed PAH specific therapy (mean exposure of 4.0 years). Conclusions: Adults with PAH and CHD often have this diagnosis made after significant delay, and have substantial medium-term morbidity and mortality. This suggests a need for children transitioning to adult care with CHD to be closely monitored for this complication.
Introduction Both surgical and medical management of children with congenital heart disease (CHD) have improved dramatically over the past decades and as such, several patients surviving with CHD through childhood into adulthood are increasing.1 Indeed, in developed nations, the adult CHD (ACHD) population now exceeds the paediatric CHD population.2 This changing demographic may place
Funding: The Registry was funded through an unrestricted grant from Actelion Pharmaceuticals Australia. Conflict of interest: None.
significant age and comorbidity related shifts in the burden of CHD. Further evaluation of the medical status and needs of this emerging population is thus important.3 Pulmonary arterial hypertension (PAH), defined as a mean pulmonary artery pressure (mPAP) ≥25 mmHg with a pulmonary artery wedge pressure ≤15 mmHg, may develop or be maintained in adulthood, in up to 10% of this population with ACHD.4–7 PAH is a significant complication of ACHD, leading to increased morbidity and mortality.8 The European Society of Cardiology has categorised PAH associated with CHD into four subcategories9 (simplistically; Eisenmenger syndrome (ES), PAH due to left to right shunts with high pulmonary © 2015 Royal Australasian College of Physicians
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Adult congenital heart disease and PAH
vascular resistance, PAH associated with small defects and PAH persisting after corrective surgery). There are very few data characterising this emerging population of adults with CHD complicated by PAH.10–13 We therefore sought to document the diagnostic features, demographics and health status of adult patients being diagnosed with CHD-associated PAH in specialist ACHD centres across Australia and New Zealand (ANZ) from 1 January 2000, by establishing a binational registry.
Methods Participants and study setting The background and methodology of the Registry have been previously published.13 Data were both retrospectively and prospectively collected from 12 contributing adult PAH/CHD centres across ANZ from March 2010 to July 2013. All patients were included (alive/deceased) if they had had a diagnosis of PAH associated with CHD (mPAP ≥25 mmHg and increased PVR >3 Wood units) in at least one lung (adjudicated by two senior paediatric and adult cardiologists) and in addition, patients had to been seen at least once in an adult centre after 1 January 2000. Four time points throughout the patient’s journey were recorded: (i) age at first diagnosis of CHD; (ii) age at onset of first symptom onset related to PAH; (iii) age at diagnosis of PAH; and (iv) age at confirmed diagnosis of PAH in the adult centre. All other parameters collected have been detailed previously.13 All efforts were made to advertise the study and we include all 12 centres managing adults with CHD across ANZ. This binational registry had complete geographical representation from all states and territories across Australia and New Zealand. All centres obtained human research ethics committee approval to conduct and contribute to the registry. During the study period, 370 subjects were evaluated for enrolment, with 10 patients excluded; eight were ‘lost to follow up’ prior to 1 January 2000 and two patients who did not have confirmed PAH. Therefore our population for data analysis was 360 patients.
Data analysis The data fields for data collection through an SSQL webbased secure database have been previously published.13 Data were summarised using standard descriptive statistics, including means, medians, standard deviations, ranges and frequencies and percentages, as appropriate. The associations between clinical and demographic features at diagnosis and mortality were tested using uniand multivariate Cox proportional hazard regression models. All analyses were undertaken using SPSS v19.0.
Results Patient demographics Table 1 summarises the demographic and diagnostic information of the 360 subjects at the time of baseline PAH diagnosis in the ACHD centre. Sixty per cent of the population were female, with the mean age of CHD diagnosed in childhood 7.9 years (±15.0 years). Eighty-five per cent of the registry population were from Caucasian background and 24% had a diagnosis of Down syndrome. Only 34% (n = 121) of the population had had prior surgical intervention and 68% (n = 246) of our population were diagnosed with Eisenmenger physiology. More than half the patients (56%) were in New York Heart Association (NYHA) functional class (FC) III at the time of presentation in the adult centre and 34% were in FC II. The mean 6-min walk test (6MWT) distance (6MWD) was 364 ± 139 metres. The predominant presenting symptoms, which could coexist, were shortness of breath (n = 303; 85%), dizziness/syncope (n = 81; 24%) and palpitations (n = 76; 21%). The majority of patients (66%) had so called simple defects, comprising 75 atrial septal defects, 122 ventricular septal defects, 52 atrioventricular septal defects and 55 persistent ductus arteriosus. The remainder had complex lesions, including, transposition of the great arteries, truncus arteriosus, tetralogy of fallot and single ventricle type hearts (many of whom had had palliative surgery prior to the diagnosis of PAH) (Fig. 1).
Time points of diagnosis The mean age at first symptom onset that could be related to PAH was 24.6 ± 16.5 years. The mean age at presentation/diagnosis of PAH in adulthood was 31.2 ± 14 years, leaving a significant delay from first symptom recognition to presentation/diagnosis in an adult centre of 6.5 ± 8.9 years (median 2.2 years) (Fig. 2).
Tests for PAH diagnosis Patients were evaluated using a variety of diagnostic tests to obtain the diagnosis of PAH associated with CHD at the adult centre. Figure 3 outlines the percentages of patients evaluated with each test assessed. Two hundred and eight (59%) patients had their PAH diagnosed through right heart catheterisation (RHC), 117 (33%) through echocardiography and the remainder through clinical evaluation (1.7%). We were unable to ascertain the exact diagnostic tests for the original pulmonary hypertension diagnosis in 7.3% of patients. Table 2 describes the haemodynamics at baseline in
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Table 1 Baseline demographics n Gender Male Female Ethnicity Caucasian Aboriginal Maori Asian African Other PHT/PAH aetiology Systemic to pulmonary shunt Developmental Other (LHOD) 6MWD Eisenmenger physiology Yes No Unknown Down syndrome Yes No Method of diagnosis RHC Echo Clinical Unknown Past CHD surgery Yes No Unknown Associated lung disease Yes No Unknown Smokers Ever Pack years Echocardiogram TR severity Trivial Mild Moderate Severe Unknown RVH Dilated RV
Subjects (%)
142 218
40 60
309 4 2 18 4 23
85.8 1.1 0.6 5 1.1 6.4
348 2 9 219
96.7 0.6 2.7 364 ± 139 metres
246 111 3
68.3 30.8 0.9
87 273
24.2 75.8
208 117 6 26
58.3 32.8 1.7 7.3
121 237 3
33.6 65.8 0.6
80 271 9
22.2 76.3 2.5
42
12 19 P/years ± 16.2†
342 73 120 52 18 75 218 224
95 20.3 34.4 14.4 5.0 20.8 64 65
†1 pack year = 20 cigarettes a day for 1 year. 6MWD, 6-min walking distance; Echo, echocardiography; LHOD, left heart obstructive disease; RHC, right heart catheterisation; RV, right ventricle; RVH, right ventricular hypertrophy; TR, tricuspid regurgitation.
those having a RHC. There were no significant differences of RHC data in those who had baseline data recorded earlier in life compared with those recoded at adult presentation.
Figure 1 Aetiology/associated congenital heart disease. ( ), Subject (N); ( ), registry (%).
Figure 2 Age at diagnosis time points.
Figure 3 Baseline tests at pulmonary arterial hypertension diagnosis in the adult centre (%).
Clinical follow up Each clinical review since 1 January 2000 or the time of diagnosis in the adult centre was recorded, including mortality status, transplantation status, NYHA functional class, changes in symptoms, need for supplemental oxygen, any hospitalisation due to PAH, results from echocardiography and 6MWT (when performed) and a commentary on prescribed medications. © 2015 Royal Australasian College of Physicians
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Table 2 Invasive haemodynamics at diagnosis of PAH
systAo (mmHg) meanAo (mmHg) systPA (mmHg) meanPA (mmHg) meanRA (mmHg) PAWP (mmHg) CI (L/min/m2) PVR (WU)
n
Base line (mean ± SD)
n
Baseline from adult centre diagnosis (mean ± SD)
123 99 159 148 137 88 72 70
107 ± 22.3 78 ± 16.6 87 ± 26.7 60 ± 20.4 7 ± 4.7 12 ± 6.5 3.2 ± 1.46 11 ± 6.9
168 136 220 211 184 118 101 97
107 ± 23.5 78 ± 16.4 87 ± 28.5 59 ± 21.8 7.22 ± 4.4 12 ± 6.3 3.06 ± 1.3 12 ± 7.6
CI, cardiac index; meanAo, mean aortic pressure; meanPA, mean pulmonary artery pressure; meanRA, mean right atrial pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; systAo, systolic aortic pressure; systPA, systolic pulmonary artery pressure.
Over the observational period we collected 2936 patient-years of follow up, collecting on average 4.5 echocardiograms, 3.9 6MWD and information from 7.0 clinic visits per patient. The mean number of echocardiograms and 6MWT was 0.9 and 0.8 respectively, per patient per year and there was an average of 1.4 clinic visits per year for each patient.
Morbidity and mortality All-cause mortality for our population was 12% at 5 years, 21% at 10 years and 31% at 15 years respectively
(Fig. 4). Thirty per cent (n = 106) of patients experienced 247 hospitalisations, representing 2.3 hospitalisations per patient hospitalised, during their follow-up period. The most common causes for hospitalisation were heart failure (21%), arrhythmias (18%), dizziness/syncope/ seizures (12%), infection/sepsis (11%) and bleeding or thrombosis (8%). A Cox proportional hazards regression model was used to evaluate potential correlates with survival. The following independent variables were tested: gender, functional class (FC), Down syndrome, surgical intervention, associated lung disease, dizziness, syncope or seizures, congestive heart failure (CHF), smoking status, simple versus complex CHD, era of diagnosis (pre and post 2007 – chosen as this was the period of introduction of PAH specific therapy) and the date of diagnosis in the adult centre (pre and post 2007). Dizziness, syncope, seizures (P = 0.035), CHF at diagnosis (P = 0.005), FC IV (P = 0.023) and later era of diagnosis (pre vs post 2007) (P = 0.012) were significantly associated with mortality on univariate analysis. In the multivariate analysis, two variables remained significant. There was a twofold increased risk of death in those patients with a diagnosis after 2007 (HR: 2.19, P = 0.026) and an almost threefold increase in risk of death in those patients with CHF at diagnosis (HR: 2.93; P = 0.008). To evaluate the potential survival bias identified from the HR calculations, we internally validated our Kaplan–Meier (KM) survival by looking at the pre and post 2007 KM estimate analysis and found an approximate 10% variation in survival, pre versus post 2007.
Figure 4 All-cause mortality.
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Figure 5 Medication ambrisentan.
utility.
( ),
Bosentan;
( ),
sildenafil;
( ),
Medications At any time point during our observational period, 43% of patients had been treated with anticoagulant therapy (aspirin and warfarin), with a mean exposure of 8.2 years. Forty per cent were prescribed diuretics for 7.2 years and 16% were prescribed digoxin for an average of 15.2 years. Seventy-three per cent of patients had been prescribed an endothelin receptor antagonist (ERA) with a mean exposure of 4.0 years (bosentan in the vast majority of these; ambrisentan or sitaxsentan in a small number only), 41% had received a phosphodiesterase type five (PDE5) inhibitor for 3.1 years (mostly sildenafil and mostly in combination with an endothelin receptor blocker) and only 4% had had prostacyclin (mostly in inhaled formulation) for an average of 3.8 years. Those remaining on therapy at the time of final follow up included 56% from the initial 73% on ERA treatment, 34% of the 41% on PDE5 inhibition and 3% of the 4% initially on prostacyclin therapy (Fig. 5). FC improved from an average of 70% FC III at the time of first PAH specific medication to 52% at the time of last visit and from 25% FC II at the start of medical therapy to 43% at the time of last visit. Seventeen per cent of those that stayed the same or improved died versus 26% in those who functionally deteriorated. There was a large range in baseline 6MWD (mean: 364 ± 139; R: 18–758; median: 375; IQR 290–456). For the group as a whole, the 6MWD revealed a steady decline in the years prior to PAH specific therapy and then stabilisation post initiation of PAH specific therapy.
Discussion This binational registry describes the demographics, diagnostic characteristics, morbidity and mortality of 360 adult patients with CHD and associated PAH. We have identified an all-cause mortality of 12%, 21% and 31%
at 5, 10 and 15 years respectively after diagnosis. We note a minimum prevalence of 14 cases of CHD-PAH per million of the population across Australia and New Zealand. There were significant delays from adult recognition of symptom onset to the presentation with or diagnosis of PAH in our adult CHD-PAH population (mean >6 years). Our registry appeared to indicate that treatment with PAH specific therapy might have had a positive impact on functionality, but did not appear to impact morbidity. There is little information describing adults living with CHD and associated PAH. The current PAH registry has limited data on the CHD population. The Dutch registry indicated an overall prevalence of PAH in the CHD population of 4%, but within the group of systematic to pulmonary or surgical shunts, the incidence was 10%.5 Recent data from a Canadian population cohort study of 38 430 patients with CHD revealed that almost 6% had a concomitant diagnosis of PAH.7 Extrapolated, it is estimated that there would be ∼32 000 patients under the age of 18 (perhaps the same over the age of 18) with CHD in Australia and within this population, one might expect ∼1600 patients living with CHD-PAH. We only report on 360 patients of the expected population with CHD-PAH. Recent data describing community prevalence of ‘allcause’ PHT estimated PAH associated with CHD to be 150 cases per million of the Australian population, equating to 3600 adults and children living with CHD-PAH. These data were derived from echocardiography and are subject to both diagnostic and epidemiological weaknesses, but nevertheless, expose a major discrepancy between those patients entered into our registry and the predicted community prevalence within this study.11 This is not surprising, given the well-documented low attendance rates of ‘at-risk’ ACHD patients at ACHD centres worldwide.14 Historically, untreated, prevalent CHD-PAH survival has been better than for those with idiopathic PAH (iPAH).15 Since the introduction of PAH specific therapy, short- to medium-term survival in iPAH appears to have improved, although survival even in those treated with combination therapy remains less than the CHD-PAH population.16 From data derived from the USA REVEAL registry, comprising of 3515 total pulmonary hypertensive patient enrolments, 353 patients with CHD-PAH were identified. The authors reported 7-year survival between 64 and 70% for repaired and unrepaired CHDPAH. We report 10- and 15-year survival of 79 and 69% and even taking into account a potential 10% survival bias; our data indicate a slightly more favourable outcome within our studied population. Only 20% of the REVEAL CHD-PAH patients had had corrective surgical repair compared with 34% of our population. Age, NYHA functional class, female preponderance, haemodynamics © 2015 Royal Australasian College of Physicians
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and the 6MWD were all similar in REVEAL compared with our registry at the time of CHD diagnosis. We have 248 ES patients (only 8% of whom had had surgical repair) compared with 151 within the REVEAL registry and this may have had a significant impact on observed survival. In addition, we describe 73% of our population being treated by PAH specific therapy during the course of our follow up, for an average exposure of 4 years. It is difficult to estimate the impact of this on survival, within this population. Several papers have described the substantial delays in diagnosis of iPAH.17–19 Consistently across Europe and the United States, a delay of ∼2.8 years has been described since 1980. The only information from Australia is a small study describing a delay in diagnosis from symptom onset of 3.9 years within the iPAH population.20 It is of significant concern that we describe an average time from symptom recognition in adulthood to patient presentation of 6 years (median 2.2 years). These delays reflect a considerable question mark surrounding the current ‘transition’ from paediatric to adult care and warrant further investigation.14 It may also be that symptoms in CHD can be ascribed to the CHD by patients and community-based physicians rather than being due to the associated PAH. The delay may consist of two aspects; delayed presentation following new onset of symptoms and possibly, a delay in a subsequent PAH diagnosis of the patient presenting with new symptoms suggestive of PAH. PAH specific therapy became available across Australia and New Zealand in 2006 through a special access scheme and the first ERA (Bosentan, Actelion Pharmaceuticals Pty Ltd, Basel, Switzerland) was listed on the Pharmaceutical Benefit Scheme (a funding mechanism) in 2008 and therefore we studied survival rates pre and post 2007 analysis. The apparent worse survival post 2007 would appear to be derived from a welldocumented prevalent population versus a less welldefined incident case population (i.e. cases documented before 2007 were a prevalent group, with better survival rates, as documented by Humbert et al.).21 The apparent role of PAH-specific medications in the observed survival requires further evaluation. The apparent increase and stabilisation in functionality (FC and 6MWD) that we have found has been demonstrated in several previous studies and it is reassuring that we were able to replicate those findings in a real-world registry.11,22–25 It is interesting and informative to note the wide range of baseline 6MWD distances within our population prior to the initiation of PAH-specific therapy (data not shown). This variance should be taken into consideration when evaluating possible selection bias from randomised controlled data and reinforces the need for better evaluation measures for this population. Further,
the range cannot be simply explained by the 24% of Down syndrome patients within this registry. In fact, Kermeen and colleagues have previously described favourable outcomes with PAH-specific therapy and Down syndrome patients, evaluating this through the 6MWT.25 Notwithstanding these apparent improvements in functional status, PAH in association with CHD has significant morbidity; 68% of surviving ACHD patients will use the emergency department over a given 5-year period and 50% will be hospitalised. Twenty-nine per cent of our population had an average of two hospitalisations, specifically related to PAH, during our follow-up period. These data suggest the true burden of disease related to PAH and CHD requires further investigation. There are several limitations to these data that warrant comment. First, the data are captured from existing centres managing CHD and PAH, which by its very nature introduces referral/selection bias within our population, although we did manage to collect data from every state of Australia and the specialist regional referral centre within New Zealand. Further, it seems apparent that our data, whilst large in current CHD-PAH registries, may not be a generalisable, representative population. Second, whilst we endeavoured to capture all deceased patients from every centre within the time period of the registry data collection, it is likely that our data are subject to a survivor bias error. In an attempt to control for this, we internally validated survival pre and post 2007 and only found a 10% preponderance for a decrease in survival post 2007; however, these data should be interpreted with caution. We also noted a significant delay in diagnosis and therefore it is likely we have missed capturing all (alive/deceased) possible registry participants. Third, we only captured hospitalisations relating to PAH and therefore are unable to comment on the complete burden of disease of this population, taking into account all hospitalisations and comorbidities. Notwithstanding these limitations, we describe the largest registry of surviving and treated population of patients with CHD-PAH, to date.
Conclusions We describe significant morbidity and mortality in adults with PAH complicating CHD. There was an average delay from appearance of symptoms related to PAH, to adult PAH presentation and diagnosis, of over 6 years. Examination of the transition from paediatric to adult care is warranted. Further, greater referral from general community specialist care to specialist care within ACHD centres may improve diagnosis rates and specific treatment of PAH.
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of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30: 2493–537. Kaemmerer H, Gorenflo M, Hoeper M, Huscher D, Ewert P, Pittrow D. [Pulmonary arterial hypertension in patients with congenital heart disease: current issues and health care situation]. Dtsch Med Wochenschr 2013; 138: 1247–52. Barst RJ, Ivy DD, Foreman AJ, McGoon MD, Rosenzweig EB. Four- and seven-year outcomes of patients with congenital heart disease-associated pulmonary arterial hypertension (from the REVEAL Registry). Am J Cardiol 2014; 113: 147–55. Manes A, Palazzini M, Leci E, Bacchi Reggiani ML, Branzi A, Galie N. Current era survival of patients with pulmonary arterial hypertension associated with congenital heart disease: a comparison between clinical subgroups. Eur Heart J 2014; 35: 716–24. Rose ML, Strange G, King I, Arnup S, Vidmar S, O’Donnell C et al. Congenital heart disease-associated pulmonary arterial hypertension: preliminary results from a novel registry. Intern Med J 2012; 42: 874–9. Wray J, Frigiola A, Bull C, Adult Congenital Heart disease Research Network (ACoRN). Loss to specialist follow-up in congenital heart disease; out of sight, out of mind. Heart 2013; 99: 485–90. Gatzoulis MA, Barst R, Fineman J, Galiè N. Eisenmenger syndrome and pulmonary arterial hypertension in adults with congenital heart disease. Curr Med Res Opin 2007; 23: S19–25. Keogh A, Strange G, Kotlyar E, Williams T, Kilpatrick D, Macdonald P et al. Survival after the initiation of combination therapy in patients with pulmonary arterial hypertension: an Australian collaborative report. Intern Med J 2011; 41: 235–44. Brown LM, Chen H, Halpern S, Taichman D, McGoon MD, Farber HW et al. Delay in recognition of pulmonary
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arterial hypertension: factors identified from the REVEAL Registry. Chest 2011; 140: 19–26. Wilkens H, Grimminger F, Hoeper M, Stahler G, Ehlken B, Plesnila-Frank C et al. Burden of pulmonary arterial hypertension in Germany. Respir Med 2010; 104: 902–10. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987; 107: 216–23. Strange G, Gabbay E, Kermeen F, Williams T, Carrington M, Stewart S et al. Time from symptoms to definitive diagnosis of idiopathic pulmonary arterial hypertension: the delay study. Pulm Circ 2013; 3: 89–94. Humbert M, Sitbon O, Yaici A, Montani D, O’Callaghan DS, Jais X et al. Survival in incident and prevalent cohorts of patients with pulmonary arterial hypertension. Eur Respir J 2010; 36: 549–55. Galie N, Beghetti M, Gatzoulis MA, Granton J, Berger RM, Lauer A et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006; 114: 48–54. Kotlyar E, Sy R, Keogh AM, Kermeen F, Macdonald PS, Hayward CS et al. Bosentan for the treatment of pulmonary arterial hypertension associated with congenital cardiac disease. Cardiol Young 2006; 16: 268–74. Gatzoulis MA, Beghetti M, Galie N, Granton J, Berger RM, Lauer A et al. Longer-term bosentan therapy improves functional capacity in Eisenmenger syndrome: results of the BREATHE-5 open-label extension study. Int J Cardiol 2008; 127: 27–32. Kermeen FD, Franks C, O’Brien K, Seale H, Hall K, McNeil K et al. Endothelin receptor antagonists are an effective long term treatment option in pulmonary arterial hypertension associated with congenital heart disease with or without trisomy 21. Heart Lung Circ 2010; 19: 595–600.
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A binational registry of adults with pulmonary arterial hypertension complicating congenital heart disease G. Strange,1,2,3 M. Rose,4 F. Kermeen,5 C. O’Donnell,6 A. Keogh,7 E. Kotlyar,7 L. Grigg,8 A. Bullock,9 P. Disney,10 N. Dwyer,11 H. Whitford,12 D. Tanous,13 C. Frampton,14 R. Weintraub3,4 and D. S. Celermajer15 1
Department of Medicine, University of Notre Dame and 9Department of Paediatric Cardiology, Royal Perth Hospital, Perth, Western Australia, Pulmonary Hypertensions Society ANZ Inc., 7Department of Cardiology, St Vincent’s Hospital, 13Department of Cardiology, Westmead Hospital, 15 Sydney Medical School, Sydney, New South Wales, 3Murdoch Children’s Research Institute, 4Department of Cardiology, Royal Children’s Hospital, 8 Department of Cardiology, Royal Melbourne Hospital, 12Department of Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria, 5Department of Respiratory Medicine, The Prince Charles Hospital, Brisbane, Queensland, 10The Royal Adelaide Hospital, Adelaide, South Australia and 11 Department of Cardiology, Royal Hobart Hospital, Hobart, Tasmania, Australia; 6Department of Cardiology, Auckland City Hospital, Auckland and 2
14
Department of Cardiology, University of Otago, Christchurch, New Zealand
Key words pulmonary arterial hypertension, PAH, congenital heart disease. Correspondence David S. Celermajer, Cardiology Department, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. Email: [email protected] Received 15 March 2015; accepted 20 May 2015. doi:10.1111/imj.12821
Abstract Background: The management of children with congenital heart disease (CHD) has improved over recent decades and several patients surviving with CHD into adulthood are increasing. In developed countries, there are now as many adults as there are children living with CHD. Pulmonary arterial hypertension (PAH) occurs in ∼5% of patients with CHD. Aim: We aimed to understand the characteristics and outcomes of this emerging population. Methods: We collected data retrospectively and prospectively from 12 contributing centres across Australia and New Zealand (2010–2013). Patients were included if they had been diagnosed with PAH and CHD and had been seen once in an adult centre after 1 January 2000. Results: Of 360 patients with CHD-PAH, 60% were female and 90% were New York Heart Association functional class II or III at the time of adult diagnosis of PAH. Mean age at diagnosis of PAH in adulthood was 31.2 ± 14 years, and on average, patients were diagnosed with PAH 6 years after symptom onset. All-cause mortality was 12% at 5 years, 21% at 10 years and 31% at 15 years. One hundred and six patients (30%) experienced 247 hospitalisations during 2936 patient years of follow up. Eighty-nine per cent of patients were prescribed PAH specific therapy (mean exposure of 4.0 years). Conclusions: Adults with PAH and CHD often have this diagnosis made after significant delay, and have substantial medium-term morbidity and mortality. This suggests a need for children transitioning to adult care with CHD to be closely monitored for this complication.
Introduction Both surgical and medical management of children with congenital heart disease (CHD) have improved dramatically over the past decades and as such, several patients surviving with CHD through childhood into adulthood are increasing.1 Indeed, in developed nations, the adult CHD (ACHD) population now exceeds the paediatric CHD population.2 This changing demographic may place
Funding: The Registry was funded through an unrestricted grant from Actelion Pharmaceuticals Australia. Conflict of interest: None.
significant age and comorbidity related shifts in the burden of CHD. Further evaluation of the medical status and needs of this emerging population is thus important.3 Pulmonary arterial hypertension (PAH), defined as a mean pulmonary artery pressure (mPAP) ≥25 mmHg with a pulmonary artery wedge pressure ≤15 mmHg, may develop or be maintained in adulthood, in up to 10% of this population with ACHD.4–7 PAH is a significant complication of ACHD, leading to increased morbidity and mortality.8 The European Society of Cardiology has categorised PAH associated with CHD into four subcategories9 (simplistically; Eisenmenger syndrome (ES), PAH due to left to right shunts with high pulmonary © 2015 Royal Australasian College of Physicians
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Adult congenital heart disease and PAH
vascular resistance, PAH associated with small defects and PAH persisting after corrective surgery). There are very few data characterising this emerging population of adults with CHD complicated by PAH.10–13 We therefore sought to document the diagnostic features, demographics and health status of adult patients being diagnosed with CHD-associated PAH in specialist ACHD centres across Australia and New Zealand (ANZ) from 1 January 2000, by establishing a binational registry.
Methods Participants and study setting The background and methodology of the Registry have been previously published.13 Data were both retrospectively and prospectively collected from 12 contributing adult PAH/CHD centres across ANZ from March 2010 to July 2013. All patients were included (alive/deceased) if they had had a diagnosis of PAH associated with CHD (mPAP ≥25 mmHg and increased PVR >3 Wood units) in at least one lung (adjudicated by two senior paediatric and adult cardiologists) and in addition, patients had to been seen at least once in an adult centre after 1 January 2000. Four time points throughout the patient’s journey were recorded: (i) age at first diagnosis of CHD; (ii) age at onset of first symptom onset related to PAH; (iii) age at diagnosis of PAH; and (iv) age at confirmed diagnosis of PAH in the adult centre. All other parameters collected have been detailed previously.13 All efforts were made to advertise the study and we include all 12 centres managing adults with CHD across ANZ. This binational registry had complete geographical representation from all states and territories across Australia and New Zealand. All centres obtained human research ethics committee approval to conduct and contribute to the registry. During the study period, 370 subjects were evaluated for enrolment, with 10 patients excluded; eight were ‘lost to follow up’ prior to 1 January 2000 and two patients who did not have confirmed PAH. Therefore our population for data analysis was 360 patients.
Data analysis The data fields for data collection through an SSQL webbased secure database have been previously published.13 Data were summarised using standard descriptive statistics, including means, medians, standard deviations, ranges and frequencies and percentages, as appropriate. The associations between clinical and demographic features at diagnosis and mortality were tested using uniand multivariate Cox proportional hazard regression models. All analyses were undertaken using SPSS v19.0.
Results Patient demographics Table 1 summarises the demographic and diagnostic information of the 360 subjects at the time of baseline PAH diagnosis in the ACHD centre. Sixty per cent of the population were female, with the mean age of CHD diagnosed in childhood 7.9 years (±15.0 years). Eighty-five per cent of the registry population were from Caucasian background and 24% had a diagnosis of Down syndrome. Only 34% (n = 121) of the population had had prior surgical intervention and 68% (n = 246) of our population were diagnosed with Eisenmenger physiology. More than half the patients (56%) were in New York Heart Association (NYHA) functional class (FC) III at the time of presentation in the adult centre and 34% were in FC II. The mean 6-min walk test (6MWT) distance (6MWD) was 364 ± 139 metres. The predominant presenting symptoms, which could coexist, were shortness of breath (n = 303; 85%), dizziness/syncope (n = 81; 24%) and palpitations (n = 76; 21%). The majority of patients (66%) had so called simple defects, comprising 75 atrial septal defects, 122 ventricular septal defects, 52 atrioventricular septal defects and 55 persistent ductus arteriosus. The remainder had complex lesions, including, transposition of the great arteries, truncus arteriosus, tetralogy of fallot and single ventricle type hearts (many of whom had had palliative surgery prior to the diagnosis of PAH) (Fig. 1).
Time points of diagnosis The mean age at first symptom onset that could be related to PAH was 24.6 ± 16.5 years. The mean age at presentation/diagnosis of PAH in adulthood was 31.2 ± 14 years, leaving a significant delay from first symptom recognition to presentation/diagnosis in an adult centre of 6.5 ± 8.9 years (median 2.2 years) (Fig. 2).
Tests for PAH diagnosis Patients were evaluated using a variety of diagnostic tests to obtain the diagnosis of PAH associated with CHD at the adult centre. Figure 3 outlines the percentages of patients evaluated with each test assessed. Two hundred and eight (59%) patients had their PAH diagnosed through right heart catheterisation (RHC), 117 (33%) through echocardiography and the remainder through clinical evaluation (1.7%). We were unable to ascertain the exact diagnostic tests for the original pulmonary hypertension diagnosis in 7.3% of patients. Table 2 describes the haemodynamics at baseline in
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Table 1 Baseline demographics n Gender Male Female Ethnicity Caucasian Aboriginal Maori Asian African Other PHT/PAH aetiology Systemic to pulmonary shunt Developmental Other (LHOD) 6MWD Eisenmenger physiology Yes No Unknown Down syndrome Yes No Method of diagnosis RHC Echo Clinical Unknown Past CHD surgery Yes No Unknown Associated lung disease Yes No Unknown Smokers Ever Pack years Echocardiogram TR severity Trivial Mild Moderate Severe Unknown RVH Dilated RV
Subjects (%)
142 218
40 60
309 4 2 18 4 23
85.8 1.1 0.6 5 1.1 6.4
348 2 9 219
96.7 0.6 2.7 364 ± 139 metres
246 111 3
68.3 30.8 0.9
87 273
24.2 75.8
208 117 6 26
58.3 32.8 1.7 7.3
121 237 3
33.6 65.8 0.6
80 271 9
22.2 76.3 2.5
42
12 19 P/years ± 16.2†
342 73 120 52 18 75 218 224
95 20.3 34.4 14.4 5.0 20.8 64 65
†1 pack year = 20 cigarettes a day for 1 year. 6MWD, 6-min walking distance; Echo, echocardiography; LHOD, left heart obstructive disease; RHC, right heart catheterisation; RV, right ventricle; RVH, right ventricular hypertrophy; TR, tricuspid regurgitation.
those having a RHC. There were no significant differences of RHC data in those who had baseline data recorded earlier in life compared with those recoded at adult presentation.
Figure 1 Aetiology/associated congenital heart disease. ( ), Subject (N); ( ), registry (%).
Figure 2 Age at diagnosis time points.
Figure 3 Baseline tests at pulmonary arterial hypertension diagnosis in the adult centre (%).
Clinical follow up Each clinical review since 1 January 2000 or the time of diagnosis in the adult centre was recorded, including mortality status, transplantation status, NYHA functional class, changes in symptoms, need for supplemental oxygen, any hospitalisation due to PAH, results from echocardiography and 6MWT (when performed) and a commentary on prescribed medications. © 2015 Royal Australasian College of Physicians
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Adult congenital heart disease and PAH
Table 2 Invasive haemodynamics at diagnosis of PAH
systAo (mmHg) meanAo (mmHg) systPA (mmHg) meanPA (mmHg) meanRA (mmHg) PAWP (mmHg) CI (L/min/m2) PVR (WU)
n
Base line (mean ± SD)
n
Baseline from adult centre diagnosis (mean ± SD)
123 99 159 148 137 88 72 70
107 ± 22.3 78 ± 16.6 87 ± 26.7 60 ± 20.4 7 ± 4.7 12 ± 6.5 3.2 ± 1.46 11 ± 6.9
168 136 220 211 184 118 101 97
107 ± 23.5 78 ± 16.4 87 ± 28.5 59 ± 21.8 7.22 ± 4.4 12 ± 6.3 3.06 ± 1.3 12 ± 7.6
CI, cardiac index; meanAo, mean aortic pressure; meanPA, mean pulmonary artery pressure; meanRA, mean right atrial pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; systAo, systolic aortic pressure; systPA, systolic pulmonary artery pressure.
Over the observational period we collected 2936 patient-years of follow up, collecting on average 4.5 echocardiograms, 3.9 6MWD and information from 7.0 clinic visits per patient. The mean number of echocardiograms and 6MWT was 0.9 and 0.8 respectively, per patient per year and there was an average of 1.4 clinic visits per year for each patient.
Morbidity and mortality All-cause mortality for our population was 12% at 5 years, 21% at 10 years and 31% at 15 years respectively
(Fig. 4). Thirty per cent (n = 106) of patients experienced 247 hospitalisations, representing 2.3 hospitalisations per patient hospitalised, during their follow-up period. The most common causes for hospitalisation were heart failure (21%), arrhythmias (18%), dizziness/syncope/ seizures (12%), infection/sepsis (11%) and bleeding or thrombosis (8%). A Cox proportional hazards regression model was used to evaluate potential correlates with survival. The following independent variables were tested: gender, functional class (FC), Down syndrome, surgical intervention, associated lung disease, dizziness, syncope or seizures, congestive heart failure (CHF), smoking status, simple versus complex CHD, era of diagnosis (pre and post 2007 – chosen as this was the period of introduction of PAH specific therapy) and the date of diagnosis in the adult centre (pre and post 2007). Dizziness, syncope, seizures (P = 0.035), CHF at diagnosis (P = 0.005), FC IV (P = 0.023) and later era of diagnosis (pre vs post 2007) (P = 0.012) were significantly associated with mortality on univariate analysis. In the multivariate analysis, two variables remained significant. There was a twofold increased risk of death in those patients with a diagnosis after 2007 (HR: 2.19, P = 0.026) and an almost threefold increase in risk of death in those patients with CHF at diagnosis (HR: 2.93; P = 0.008). To evaluate the potential survival bias identified from the HR calculations, we internally validated our Kaplan–Meier (KM) survival by looking at the pre and post 2007 KM estimate analysis and found an approximate 10% variation in survival, pre versus post 2007.
Figure 4 All-cause mortality.
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Figure 5 Medication ambrisentan.
utility.
( ),
Bosentan;
( ),
sildenafil;
( ),
Medications At any time point during our observational period, 43% of patients had been treated with anticoagulant therapy (aspirin and warfarin), with a mean exposure of 8.2 years. Forty per cent were prescribed diuretics for 7.2 years and 16% were prescribed digoxin for an average of 15.2 years. Seventy-three per cent of patients had been prescribed an endothelin receptor antagonist (ERA) with a mean exposure of 4.0 years (bosentan in the vast majority of these; ambrisentan or sitaxsentan in a small number only), 41% had received a phosphodiesterase type five (PDE5) inhibitor for 3.1 years (mostly sildenafil and mostly in combination with an endothelin receptor blocker) and only 4% had had prostacyclin (mostly in inhaled formulation) for an average of 3.8 years. Those remaining on therapy at the time of final follow up included 56% from the initial 73% on ERA treatment, 34% of the 41% on PDE5 inhibition and 3% of the 4% initially on prostacyclin therapy (Fig. 5). FC improved from an average of 70% FC III at the time of first PAH specific medication to 52% at the time of last visit and from 25% FC II at the start of medical therapy to 43% at the time of last visit. Seventeen per cent of those that stayed the same or improved died versus 26% in those who functionally deteriorated. There was a large range in baseline 6MWD (mean: 364 ± 139; R: 18–758; median: 375; IQR 290–456). For the group as a whole, the 6MWD revealed a steady decline in the years prior to PAH specific therapy and then stabilisation post initiation of PAH specific therapy.
Discussion This binational registry describes the demographics, diagnostic characteristics, morbidity and mortality of 360 adult patients with CHD and associated PAH. We have identified an all-cause mortality of 12%, 21% and 31%
at 5, 10 and 15 years respectively after diagnosis. We note a minimum prevalence of 14 cases of CHD-PAH per million of the population across Australia and New Zealand. There were significant delays from adult recognition of symptom onset to the presentation with or diagnosis of PAH in our adult CHD-PAH population (mean >6 years). Our registry appeared to indicate that treatment with PAH specific therapy might have had a positive impact on functionality, but did not appear to impact morbidity. There is little information describing adults living with CHD and associated PAH. The current PAH registry has limited data on the CHD population. The Dutch registry indicated an overall prevalence of PAH in the CHD population of 4%, but within the group of systematic to pulmonary or surgical shunts, the incidence was 10%.5 Recent data from a Canadian population cohort study of 38 430 patients with CHD revealed that almost 6% had a concomitant diagnosis of PAH.7 Extrapolated, it is estimated that there would be ∼32 000 patients under the age of 18 (perhaps the same over the age of 18) with CHD in Australia and within this population, one might expect ∼1600 patients living with CHD-PAH. We only report on 360 patients of the expected population with CHD-PAH. Recent data describing community prevalence of ‘allcause’ PHT estimated PAH associated with CHD to be 150 cases per million of the Australian population, equating to 3600 adults and children living with CHD-PAH. These data were derived from echocardiography and are subject to both diagnostic and epidemiological weaknesses, but nevertheless, expose a major discrepancy between those patients entered into our registry and the predicted community prevalence within this study.11 This is not surprising, given the well-documented low attendance rates of ‘at-risk’ ACHD patients at ACHD centres worldwide.14 Historically, untreated, prevalent CHD-PAH survival has been better than for those with idiopathic PAH (iPAH).15 Since the introduction of PAH specific therapy, short- to medium-term survival in iPAH appears to have improved, although survival even in those treated with combination therapy remains less than the CHD-PAH population.16 From data derived from the USA REVEAL registry, comprising of 3515 total pulmonary hypertensive patient enrolments, 353 patients with CHD-PAH were identified. The authors reported 7-year survival between 64 and 70% for repaired and unrepaired CHDPAH. We report 10- and 15-year survival of 79 and 69% and even taking into account a potential 10% survival bias; our data indicate a slightly more favourable outcome within our studied population. Only 20% of the REVEAL CHD-PAH patients had had corrective surgical repair compared with 34% of our population. Age, NYHA functional class, female preponderance, haemodynamics © 2015 Royal Australasian College of Physicians
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and the 6MWD were all similar in REVEAL compared with our registry at the time of CHD diagnosis. We have 248 ES patients (only 8% of whom had had surgical repair) compared with 151 within the REVEAL registry and this may have had a significant impact on observed survival. In addition, we describe 73% of our population being treated by PAH specific therapy during the course of our follow up, for an average exposure of 4 years. It is difficult to estimate the impact of this on survival, within this population. Several papers have described the substantial delays in diagnosis of iPAH.17–19 Consistently across Europe and the United States, a delay of ∼2.8 years has been described since 1980. The only information from Australia is a small study describing a delay in diagnosis from symptom onset of 3.9 years within the iPAH population.20 It is of significant concern that we describe an average time from symptom recognition in adulthood to patient presentation of 6 years (median 2.2 years). These delays reflect a considerable question mark surrounding the current ‘transition’ from paediatric to adult care and warrant further investigation.14 It may also be that symptoms in CHD can be ascribed to the CHD by patients and community-based physicians rather than being due to the associated PAH. The delay may consist of two aspects; delayed presentation following new onset of symptoms and possibly, a delay in a subsequent PAH diagnosis of the patient presenting with new symptoms suggestive of PAH. PAH specific therapy became available across Australia and New Zealand in 2006 through a special access scheme and the first ERA (Bosentan, Actelion Pharmaceuticals Pty Ltd, Basel, Switzerland) was listed on the Pharmaceutical Benefit Scheme (a funding mechanism) in 2008 and therefore we studied survival rates pre and post 2007 analysis. The apparent worse survival post 2007 would appear to be derived from a welldocumented prevalent population versus a less welldefined incident case population (i.e. cases documented before 2007 were a prevalent group, with better survival rates, as documented by Humbert et al.).21 The apparent role of PAH-specific medications in the observed survival requires further evaluation. The apparent increase and stabilisation in functionality (FC and 6MWD) that we have found has been demonstrated in several previous studies and it is reassuring that we were able to replicate those findings in a real-world registry.11,22–25 It is interesting and informative to note the wide range of baseline 6MWD distances within our population prior to the initiation of PAH-specific therapy (data not shown). This variance should be taken into consideration when evaluating possible selection bias from randomised controlled data and reinforces the need for better evaluation measures for this population. Further,
the range cannot be simply explained by the 24% of Down syndrome patients within this registry. In fact, Kermeen and colleagues have previously described favourable outcomes with PAH-specific therapy and Down syndrome patients, evaluating this through the 6MWT.25 Notwithstanding these apparent improvements in functional status, PAH in association with CHD has significant morbidity; 68% of surviving ACHD patients will use the emergency department over a given 5-year period and 50% will be hospitalised. Twenty-nine per cent of our population had an average of two hospitalisations, specifically related to PAH, during our follow-up period. These data suggest the true burden of disease related to PAH and CHD requires further investigation. There are several limitations to these data that warrant comment. First, the data are captured from existing centres managing CHD and PAH, which by its very nature introduces referral/selection bias within our population, although we did manage to collect data from every state of Australia and the specialist regional referral centre within New Zealand. Further, it seems apparent that our data, whilst large in current CHD-PAH registries, may not be a generalisable, representative population. Second, whilst we endeavoured to capture all deceased patients from every centre within the time period of the registry data collection, it is likely that our data are subject to a survivor bias error. In an attempt to control for this, we internally validated survival pre and post 2007 and only found a 10% preponderance for a decrease in survival post 2007; however, these data should be interpreted with caution. We also noted a significant delay in diagnosis and therefore it is likely we have missed capturing all (alive/deceased) possible registry participants. Third, we only captured hospitalisations relating to PAH and therefore are unable to comment on the complete burden of disease of this population, taking into account all hospitalisations and comorbidities. Notwithstanding these limitations, we describe the largest registry of surviving and treated population of patients with CHD-PAH, to date.
Conclusions We describe significant morbidity and mortality in adults with PAH complicating CHD. There was an average delay from appearance of symptoms related to PAH, to adult PAH presentation and diagnosis, of over 6 years. Examination of the transition from paediatric to adult care is warranted. Further, greater referral from general community specialist care to specialist care within ACHD centres may improve diagnosis rates and specific treatment of PAH.
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