Increasing Mortality Burden among Adults with Complex Congenital Heart Disease

117 ORIGINAL ARTICLES Increasing Mortality Burden among Adults with Complex Congenital Heart Disease Matthias Greutmann, MD,* 1 Daniel Tobler, MD, 1 Adrienne H. Kovacs, PhD, Mehtap Greutmann-Yantiri, MD, Sarah R. Haile, PhD, Leonhard Held, PhD, Joan Ivanov, MSc, PhD, ** William G. Williams, MD, Erwin N. Oechslin, MD, Candice K. Silversides, MD, and Jack M. Colman, MD *Adult Congenital Heart Disease Program, University Hospital Zurich, Zurich, Switzerland; Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada; Adult Congenital Heart Disease Clinic, University Hospital Basel, Basel, Switzerland; Division of Biostatistics, Institute for Social and Preventive Medicine, University of Zurich, Zurich, Switzerland; Clinical Trials Unit, Kantonsspital St. Gallen, St. Gallen, Switzerland; **Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Department of Cardiovascular Surgery, Hospital for Sick Children, Toronto, Ontario, Canada ABSTRACT Background. Progress in management of congenital heart disease has shifted mortality largely to adulthood. However, adult survivors with complex congenital heart disease are not cured and remain at risk of premature death as young adults. Thus, our aim was to describe the evolution and mortality risk of adult patient cohorts with complex congenital heart disease. Methods. Among 12 644 adults with congenital heart disease followed at a single center from 1980 to 2009, 176 had Eisenmenger syndrome, 76 had unrepaired cyanotic defects, 221 had atrial switch operations for transposition of the great arteries, 158 had congenitally corrected transposition of the great arteries, 227 had Fontan palliation, and 789 had repaired tetralogy of Fallot. We depict the 30-year evolution of these 6 patient cohorts, analyze survival probabilities in adulthood, and predict future number of deaths through 2029. Results. Since 1980, there has been a steady increase in numbers of patients followed, except in cohorts with Eisenmenger syndrome and unrepaired cyanotic defects. Between 1980 and 2009, 308 patients in the study cohorts (19%) died. At the end of 2009, 85% of survivors were younger than 50 years. Survival estimates for all cohorts were markedly lower than for the general population, with important differences between cohorts. Over the upcoming two decades, we predict a substantial increase in numbers of deaths among young adults with subaortic right ventricles, Fontan palliation, and repaired tetralogy of Fallot. Conclusions. Anticipatory action is needed to prepare clinical services for increasing numbers of young adults at risk of dying from complex congenital heart disease. Key Words. Adult Congenital Heart Disease; Congenital Heart Surgery; Mortality; Outcomes Introduction Complex congenital heart defects affect about 0.6% of newborns, with stable incidence over time. 1,2 Most affected patients are now expected to survive to adulthood. 3,4 However, adults with repaired complex congenital heart lesions and with 1 These authors contributed equally to the study design, data interpretation, and manuscript preparation. unrepaired cyanotic lesions (including large shunt lesions complicated by Eisenmenger syndrome) remain at risk for long-term complications and are at increased risk for death as young adults. 5 8 Surgical repair techniques for complex congenital heart lesions were introduced several decades ago and have subsequently undergone continuous modification. Thus, cohorts of adult survivors are still emerging and evolving in terms 2014 The Authors. Congenital Heart Disease Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

118 of numbers, age distribution, complexity, previous interventional management, and survival patterns. In previous analyses of deaths in adults with congenital heart disease, cohorts with Eisenmenger syndrome, unrepaired cyanotic heart defects, atrial switch operations for transposition of the great arteries, congenitally corrected transposition of the great arteries, Fontan palliation for univentricular physiology, and repaired tetralogy of Fallot contributed disproportionately to the number of young adults dying from their disease. 5,6,8,9 Understanding the evolution of such adult patient cohorts and their mortality risk is essential for planning future care and research. The aims of this study were (1) to examine the 30-year evolution of 6 cohorts of adult survivors of common complex congenital heart lesions at a large tertiary care center for adults with congenital heart disease; (2) to analyze survival probabilities in these patient cohorts; and (3) to predict future trends in numbers of deaths over the upcoming two decades. Methods Database and Patient Cohorts The Toronto Congenital Cardiac Centre for Adults at Toronto General Hospital was founded in 1959. From its inception, it has collaborated closely with the Toronto Hospital for Sick Children (SickKids), which is the largest pediatric cardiology center in Canada. At SickKids, congenital cardiac surgery began in 1944, and the first open-heart operation using a heart lung machine took place in 1958. SickKids surgeons have performed 80 90% of all congenital cardiac surgical procedures for the province of Ontario, Canada. Over the study period, the population in Ontario increased from 9 million to 13 million in 2009. The clinical and administrative database at the Toronto Congenital Cardiac Centre for Adults includes all adults with congenital heart disease ever followed by the program, whether strictly ambulatory or as inpatients or both. It contains information about the anatomical cardiac diagnoses and previous surgical and nonsurgical treatment history. As well, the database is used to track follow-up visits. If patients do not attend scheduled follow-up visits they and, as necessary, their alternate contacts and general practitioners are contacted by administrative staff. Survival status is regularly updated. The mode of death of patients Greutmann et al. who died at our institution up to 1996 has previously been reported. 6 In the past, survival of children with complex congenital heart disease was critically dependent on the availability of surgical repair at a given center. In the early days of surgical repair, improving perioperative care led to increased survival of affected children. In contrast, long-term survival of those who survived the operation and early complications, reaching adulthood, was not further impacted by era of birth cohort. 10 12 Indeed, a recent study from Belgium demonstrated that survival beyond the age of 18 years was completely unaffected by birth cohort. 13 For this reason, outcomes related to birth cohort were not the focus of this study. After obtaining institutional research ethics board approval, we used the database to identify adult patient cohorts with one of the following 6 diagnoses previously shown to contribute to a high burden of premature death in adulthood: 5,6,8,9 (1) Eisenmenger syndrome; (2) unrepaired cyanotic heart defect; (3) complete transposition of the great arteries after atrial switch repair; (4) congenitally corrected transposition of the great arteries; (5) Fontan palliation for single ventricle physiology; and (6) repaired tetralogy of Fallot. For each cohort, we examined the evolution of numbers of patients and their age distribution between the years 1980 and 2009. Survival probabilities for each patient cohort were compared to the age- and gender-matched general Canadian population. 14 Based on these survival probabilities, we predicted future numbers of deaths in the years 2010 through 2029. Statistical Methods All analyses were performed in the R programming language. 15 Patient characteristics have been presented as medians (with interquartile range) for continuous variables and as counts (with percentage) for nominal variables. Survival Analysis Survival of adult patients ( 18 years) within each of the 6 disease cohorts was estimated by computing Kaplan Meier survival curves using age as time scale, with Canadian age- and gendermatched survival data used for comparison (18- year-old Canadians in 1980 with the same sex distribution). 14,16 Individual survival times were both left-truncated and right-censored, as is appropriate for such an observational study. 16 18 In such Kaplan Meier estimates, survival probability

Mortality Burden of Adults with Complex CHD 119 is assumed to be independent of age at entry into the database; for example, a 35-year-old patient who was referred to the adult clinic at age 18 is assumed to have the same survival probability as a patient with the same diagnosis who was first referred at age 35. However, in clinical practice, patients who are referred to the adult clinic not through routine transition from pediatric care at around age 18 but rather later in life may be referred in response to a clinical complication, thus introducing bias. In order to minimize this bias, we computed survival estimates only for patients who entered the cohort at <30 years of age. A Cox regression analysis using age at entry as an explanatory variable was also performed to test the assumption that survival probability was independent of age of admission to the adult clinic. 18 Estimates of Future Deaths Using the calculated survival estimates, we predicted the number of future deaths expected to occur at our center in the 6 study cohorts between 2010 and 2029. We considered that patients at risk for death would include (1) those actively followed at our center at the end of 2009 and (2) those expected to be newly referred over the upcoming two decades. New patients are expected to be referred into all patient cohorts each year, except for patients with an atrial switch procedure for transposition of the great arteries, because this operation was superseded by the arterial switch operation after 1987. Since the incidence of congenital heart disease at birth is relatively stable and most patients now survive to adulthood, the increment of new patients within each cohort was anticipated by assuming that the number of new patients per year would match the average annual number of new patients referred to our center between 2005 and 2009, with similar age distribution. 13 Results Patient Characteristics Between 1980 and 2009, 12 644 adults with congenital heart disease were followed at our center. Of these, 1647 (13%) had one of the 6 index diagnoses and constituted the 6 study cohorts. These 6 index diagnoses were previously shown to contribute disproportionally to cardiovascular mortality in adults with congenital heart disease. 5,6 In this study, these 6 cohorts accounted for 61% (308/ 507) of all deaths in patients followed at our center. Baseline characteristics are given in Table 1. Evolution of Patient Cohorts The numbers of patients and the relative age distribution in each study cohort have evolved over the last 3 decades, as illustrated in Figure 1. At the end of the data acquisition period (2009), most patients (85%) were still younger than 50 years. There were substantial differences in the direction and magnitude of change in patient numbers and age distribution among the 6 study cohorts. Between and 2009, the numbers of actively followed patients with Eisenmenger syndrome and unrepaired cyanotic defects decreased by 8% and 27%. Respectively, whereas within the 4 other disease cohorts, the number of patients increased by 42% to 94%. Survival 1980 2009 Between 1980 and 2009, 308/1647 patients (19%) within one of the 6 study cohorts died. Of all deaths, 90% could be attributed to the underlying cardiac disease. In 5 patients (2%), the exact cause of death could not be ascertained. Twenty-five patients (8%) died of noncardiac cause. Thirtyfive percent of patients died suddenly, and 13% died perioperatively at the time of cardiac surgery. Figure 2 depicts Kaplan Meier survival plots for patients within the study cohorts who were referred to the adult clinic at age <30 years, as compared with survival for the Canadian age- and gender-matched general population. Survival was significantly lower in each of the 6 disease cohorts than in the general population, but it differed substantially among the cohorts. A Cox regression analysis confirmed that survival probability in the defined cohorts was independent of age at admission to the adult clinic for each of the cohorts (P >.4 for all patient cohorts). Estimate of Future Deaths 2010 2029 At the end of 2009, the 6 study cohorts included 1052 actively followed patients (Table 1). The average number of newly referred patients per annum in each of the 6 study cohorts between 2005 and 2009, shown in Table 1, was used to estimate growth in future cohorts. As shown in Table 1, the observed numbers of deaths across all 6 study cohorts in the three decades since 1980 were 46, 124, and 138. Within these same 6 cohorts, mortality estimates for the decade from 2010 to 2019 predict 210 deaths, and those from 2020 to 2029 predict 247 deaths (an average of 25 deaths per year). The observed numbers of deaths from 1980 to 2009 and predicted numbers of

120 Greutmann et al. Table 1. Baseline Characteristics of Patients in the 6 Study Cohorts Totals for All 6 Cohorts Eisenmenger Syndrome Non-Eisenmenger Cyanotic Defects Transposition of the Great Arteries after Atrial Switch Procedures Congenitally Corrected Transposition of the Great Arteries Fontan Palliation for Single Ventricle Physiology Repaired Tetralogy of Fallot in the database 1647 176 76 221 158 227 789 Male gender, n (%) 919 (56) 74 (42) 39 (51) 151 (68) 85 (54) 122 (54) 448 (57) Age at entry into database, 21.1 (18.9 28.7) 30.9 (23.1 40.0) 21.3 (19.1 28.7) 19.6 (18.7 23.6) 24.6 (19.0 36.5) 19.1 (18.6 21.3) 21.3 (19.0 33.0) median (interquartile range) who 1219 (74) 86 (49) 60 (79) 207 (94) 100 (63) 214 (94) 552 (70) entered the database <30 years, n (%) All-cause mortality, n (%) 308/1647 (19) 105/176 (60) 43/76 (57) 28/221 (13) 35/158 (22) 43/227 (19) 54/789 (7) Number of deaths per decade, n (%) 1980 1989 46 (15) 19 (18) 3 (7) 4 (14) 6 (17) 9 (21) 5 (9) 1990 124 (40) 49 (47) 16 (37) 9 (32) 16 (46) 12 (28) 22 (41) 2000 2009 138 (45) 37 (35) 24 (56) 16 (57) 13 (37) 22 (51) 27(50) Age at death (years), 37.0 ± 13.2 39.1 ± 12.1 34.8 ± 11.7 27.7 ± 7.6 37.9 ± 13.5 29.7 ± 8.5 44.8 ± 15.9 mean ± SD 1980 1989 30.8 ± 8.8 32.4 ± 10.1 28.9 ± 7.4 26.0 ± 9.2 33.0 ± 8.5 24.8 ± 3.7 37.8 ± 5.1 1990 37.2 ± 13.1 39.4 ± 10.8 31.1 ± 8.1 22.5 ± 3.8 39.0 ± 13.6 30.6 ± 8.5 44.9 ± 17.5 2000 2009 38.8 ± 13.9 42.2 ± 13.5 38.0 ± 13.3 31.1 ± 7.4 38.8 ± 15.6 31.1 ± 9.3 46.1 ± 16.0 Annual number of new 67 (54 89) 5 (1 5) 1 (0 2) 5 (3 9) 7 (4 10) 13 (9 17) 34 (25 57) patients between 2005 and 2009, median (range) Actively followed patients at the end of 2009, n 1052 45 24 156 99 151 577 P <.001 for comparisons between groups.

Mortality Burden of Adults with Complex CHD 121 year All patients 2009 > 60 years (n = 1052) (n = 690) 1989 (n = 322) 0 100 200 300 400 500 51-60 years 41-50 years 31-40 years 18-30 years Eisenmenger syndrome Non-Eisenmenger cyanotic defects 2009 (n = 45) 2009 (n = 24) year (n = 49) year (n = 33) 1989 1989 (n = 45) (n = 29) 0 50 100 0 50 100 Complete transposition of the great arteries after atrial switch operations Congenitally corrected transposition of the great arteries 2009 2009 (n = 156) (n = 99) ar ye (n = 110) ar ye (n = 67) 1989 1989 (n = 23) (n = 28) 0 50 100 0 50 100 Fontan palliation for single ventricle physiology Repaired tetralogy of Fallo 2009 2009 (n = 151) (n = 577) year (n = 78) year (n = 343) 1989 (n = 36) 1989 (n = 161) 0 50 100 0 50 100 150 200 250 Figure 1. Number and age distribution of patients alive at the end of each decade, according to cardiac diagnosis.

122 Greutmann et al. Figure 2. Survival of cohorts of adults with complex congenital heart disease compared to age- and gender-matched Canadian population. Graphs show Kaplan Meier survival estimates of patients that entered the cohort at age <30 years (mean survival is depicted by solid line with 95% confidence intervals shown as dashed lines). Survival in the general Canadian population is depicted by the solid bold line. TGA, transposition of the great arteries; EM, Eisenmenger; UVH, univentricular heart. deaths extended to 2029 are shown in Figure 3. A substantial increase in numbers of deaths is expected in patients with transposition complexes with subaortic right ventricles, those with Fontan palliation, and those with repaired tetralogy of Fallot, whereas the number of deaths in the cohorts with Eisenmenger syndrome and unrepaired cyanotic defects is anticipated to remain relatively constant. Discussion This analysis of 6 selected adult high-risk cohorts with complex congenital heart disease that accounted for 61% of all adult congenital heart disease deaths at our center begins two decades after the introduction of the heart lung machine at our center and thus depicts the evolution of patient numbers and outcomes from the

Mortality Burden of Adults with Complex CHD 123 90 80 aths ber of de Num 70 60 1980-89 50 40 30 20 1990-99 2000-09 2010-19 10 2020-29 0 Figure 3. Past and future deaths in adults followed in a large tertiary care center for adults with congenital heart disease, 1980 2029. Number of observed deaths over the last 3 decades (1980 2009) shown in shades of grey and number of expected deaths between 2010 2019 and 2020 2029 in hatched shades of grey, stratified for the 6 study cohorts. cctga, congenitally corrected transposition of the great arteries; TGA. transposition of the great arteries; EM, Eisenmenger. beginning of the modern era of adult congenital heart disease treatment to the present day. Previous studies have demonstrated that modern heart surgery has substantially decreased early childhood mortality of patients with complex congenital heart disease. 3 This study demonstrates for the first time that a substantial number of patients with complex congenital heart disease reaching adulthood still face premature death as young adults. Given the ongoing increase in the number of survivors reaching adulthood and the ageing of existing cohorts, we predict a substantial increase in the number of young adults at risk for premature death over the next two decades. In the decade 1980 1989, a total of 46 adults among the 6 study cohorts died, which accounts for less than 5 deaths every year at our center, yet we predict that in the decade 2020 2029 that number will increase fivefold, to 25 deaths annually. That certain other inherited and acquired diseases such as AIDS or cystic fibrosis put young adults at risk of death has previously been recognized, but until now this has not clearly been described in adults with congenital heart disease, even though the magnitude of the phenomenon in the congenital heart disease population is greater. As examples, in the year 2009, across all of Canada (population 33 million), 25 adults died from AIDS, and in 2010, 40 adults and children died from cystic fibrosis. 19,20 Adults with complex congenital heart disease require specialized care, and many will experience cardiovascular complications requiring hospital admissions and interventions. 5,21 24 Such a large, rapidly expanding group of complex patients at risk for death as young adults will profoundly increase need for inpatient and ambulatory resources at all tertiary care centers looking after such patients. Differing Evolution of Future Patient Cohorts In developed countries, children with simple defects are almost always diagnosed early in life and offered surgical repair in a timely manner. This has led to a progressive decrease in the number of patients with Eisenmenger syndrome, a trend which is predicted to continue over the next few decades. Similarly, most patients born in recent decades with complex cyanotic lesions have undergone surgical repair relieving cyanosis. 25,26 This is emphasized by our observation that by the end of 2009 the majority of patients with Eisenmenger syndrome or unrepaired cyanotic heart defects that had ever been seen at our center had already died. In contrast, the majority of patients in the other studied cohorts were still alive at the end of 2009. Except for patients who had undergone an atrial switch operation, the cohorts were expanding in size, contributing to an increasing pool of patients at risk for future cardiovascular complications and premature death. Pediatric surgical and interventional techniques continue to evolve. The arterial switch operations for transposition of the great arteries, modifications of the Fontan procedure such as the lateral tunnel technique and the total

124 extracardiac cavopulmonary connection, and the Norwood procedure and its variants for palliation of hypoplastic left heart syndrome have resulted in additional novel patient cohorts with different residua and sequelae. These cohorts were not included in our analysis because they have not yet reached adulthood in large numbers, and their long-term outcomes remain to be determined. However, surely they will also be at risk for cardiovascular complications in adulthood. 27,28 Future Challenges in Patient Care The pioneers of the past succeeded in converting deadly congenital cardiac lesions into treatable conditions. Consequently, survival to adulthood is now expected. This is one of the most remarkable success stories in modern medicine. As shown in this study, that very success has resulted in a large and growing population of young adult survivors with congenital heart disease at risk for premature death. To extend the success story of past decades into the future will require new resources for patient care and a major, concerted, and collaborative effort in research. Many of the important unanswered questions, such as optimal medical management and optimal timing for reoperation or transplantation, will be answered only by wellconducted multicenter studies. Only the recognition of the scope of the problem by health care politicians will allow adequate funding of such important research. Given the large number of patients at risk today, this issue is an urgent one. Adults with congenital heart disease, particularly those with complex lesions, have already been shown to be responsible for increasing numbers of hospital admissions. 21,24,29,30 Medical care for such young adults poses unfamiliar challenges to our health care system. 22 While specialized multidisciplinary care for these complex patients during childhood is well established at pediatric centers, only recently has the need for such care in adulthood begun to be recognized. 31,32 Providers will be confronted with adults suffering from multisystem disease who are younger and at a different stage of life than most with acquired heart disease. These young patients often die in hospital and have historically received aggressive medical treatment even in the end stage of disease. 22 Optimal management requires close collaboration between cardiologists specialized in adult congenital heart disease, specialized congenital heart surgeons, and many other subspecialties. 14 Such patients, who carry their chronic and sometimes life-threatening conditions into middle age, often present with Greutmann et al. uncommon or novel medical problems requiring innovative management strategies. At present, infrastructure, resources, and manpower are inadequate to provide and coordinate the needed complex interdisciplinary care for this rapidly expanding and evolving group of adult survivors of previously fatal childhood disease. 31,32 Limitations Given that our data were derived from adults followed at a single large tertiary center, our findings may not be applicable to the entire population of adults with congenital heart disease. However, our experience will parallel that of other tertiary care centers for adults with congenital heart disease in the developed world. 33 35 Because the cohorts that were the focus of this study accounted for only 61% of deaths at our center, the entire present and future burden of deaths of patients under our care is and will be greater than has been described here. Premature mortality may be seen even in patients with less complex disease. 8 Also, most patients after Fontan palliation and atrial switch operations are still young, and as shown for patients with repaired tetralogy of Fallot, the hazard for death is not constant as the studied cohorts age. 11 Given the lack of formal transition programs from pediatric to adult cardiology centers before the 1990s, many infant survivors with complex congenital heart disease had lapses in specialist care during adulthood. 36 A recent study in adult survivors after repair of tetralogy of Fallot in the United Kingdom suggests that mortality was higher in the 24% of adults who were not under specialist care in adulthood. 37 With the emergence of specialized centers for adults with congenital heart disease, adult survivors with complex congenital heart disease who did not initially transition from pediatric cardiology care will be referred back to such centers late, particularly when complications occur. These late referrals will increase the workload of existing tertiary care centers. Thus, we likely underestimate the magnitude of increase in late mortality risk in these cohorts. Indeed, a recent study has shown that in adults with congenital heart disease, hospital admissions and interventions increase with advancing age. 38 With ageing of patient cohorts, the emergence of acquired heart disease on top of the congenital cardiac condition may further increase mortality risks. The survival analysis was limited to patients who entered the cohort at age <30 years. As a consequence, survival estimates could be developed only

Mortality Burden of Adults with Complex CHD 125 until the age of 60, notwithstanding that congenital heart disease patients certainly survive longer. Additional differences in mortality compared to the general population may emerge over time that cannot be predicted from the current study. Our data do not provide lesion-specific outcome data for individual patients, as no lesion-specific factors (ventricular function, associated lesions, pulmonary hypertension, etc.) were analyzed. Our predictions are based on current clinical practice. Improvement in medical, surgical, and interventional care may favorably modify longterm trends in survival of adults with complex congenital heart disease. Conclusions Cohorts of adult survivors with complex congenital heart disease are expanding, evolving, and aging. Their risk of death in young adulthood far exceeds that familiar in acquired heart disease clinical practice. The burden of care will continue to increase over at least the next two decades. Anticipatory action is needed to ensure optimal multidisciplinary care for this novel and complex group of young adults. Author Contributions Matthias Greutmann: Conception and design of the study, analysis and interpretation of the data, drafting of the manuscript. Daniel Tobler: Conception and design of the study, analysis and interpretation of the data, drafting of the manuscript. Adrienne H. Kovacs: Conception and design of the study, revising the manuscript critically for important intellectual content. Mehtap Greutmann-Yantiri: Conception and design of the study, revising the manuscript critically for important intellectual content. Sarah R. Haile: Statistical analysis and interpretation of the data, revising the manuscript critically for important intellectual content. Leonhard Held: Statistical analysis and interpretation of the data, revising the manuscript critically for important intellectual content. Joan Ivanov: Conception and design of the study, statistical analysis and interpretation of the data. William G. Williams: Revising the manuscript critically for important intellectual content. Erwin N. Oechslin: Revising the manuscript critically for important intellectual content. Candice K. Silversides: Revising the manuscript critically for important intellectual content. Jack M. Colman: Conception and design of the study, revising the manuscript critically for important intellectual content, final approval of the manuscript submitted. Corresponding Author: Jack M. Colman, MD, Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University Health Network, 5N519, 585 University Avenue, Toronto, ON M5G 2N2, Canada. Tel: 416-586-4800x5288; Fax: 416-586- 5968; E-mail: j.colman@utoronto.ca Conflict of interest: None. Accepted in final form: May 31, 2014. References 1 Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol. 2002;39:1890 1900. 2 van der Linde D, Konings EE, Slager MA, et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. JAm Coll Cardiol. 2011;58:2241 2247. 3 Khairy P, Ionescu-Ittu R, Mackie AS, Abrahamowicz M, Pilote L, Marelli AJ. Changing mortality in congenital heart disease. J Am Coll Cardiol. 2010;56:1149 1157. 4 Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation. 2007;115:163 172. 5 Engelfriet P, Boersma E, Oechslin E, et al. The spectrum of adult congenital heart disease in Europe: morbidity and mortality in a 5 year follow-up period. The Euro Heart Survey on Adult Congenital Heart Disease. Eur Heart J. 2005;26:2325 2333. 6 Oechslin EN, Harrison DA, Connelly MS, Webb GD, Siu SC. Mode of death in adults with congenital heart disease. Am J Cardiol. 2000;86:1111 1116. 7 Inuzuka R, Diller GP, Borgia F, et al. Comprehensive use of cardiopulmonary exercise testing identifies adults with congenital heart disease at increased mortality risk in the medium term. Circulation. 2012;125:250 259. 8 Verheugt CL, Uiterwaal CS, van der Velde ET, et al. Mortality in adult congenital heart disease. Eur Heart J. 2010;31:1220 1229. 9 Daliento L, Somerville J, Presbitero P, et al. Eisenmenger syndrome. Factors relating to deterioration and death. Eur Heart J. 1998;19:1845 1855. 10 Williams WG, McCrindle BW, Ashburn DA, Jonas RA, Mavroudis C, Blackstone EH. Outcomes of 829

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