Journal of Cardiology 63 (2014) 286–290

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Original article

Survey of the current status and management of Eisenmenger syndrome: A Japanese nationwide survey Taku Inohara (MD) a,b,∗ , Koichiro Niwa (MD, PhD, FJCC) b , Atsushi Yao (MD, PhD) c , Ryo Inuzuka (MD, PhD) d , Hisanori Sakazaki (MD) e , Hideo Ohuchi (MD, PhD, FJCC) f , Kei Inai (MD, PhD, FJCC) g , Research Committee of the Japanese Society of Adult Congenital Heart Disease a

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan Department of Cardiology, Cardiovascular Center, St. Luke’s International Hospital, Tokyo, Japan c Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan d Department of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, Japan e Department of Pediatric Cardiology, Hyogo Prefectural Amagasaki Hospital, Amagasaki, Japan f Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan g Department of Pediatric Cardiology, Tokyo Women’s Medical University, Tokyo, Japan b

a r t i c l e

i n f o

Article history: Received 2 May 2013 Received in revised form 26 August 2013 Accepted 28 August 2013 Available online 18 October 2013 Keywords: Congenital heart disease Pulmonary hypertension Eisenmenger syndrome Pulmonary vasodilator Heart failure

a b s t r a c t Background: The management of Eisenmenger syndrome (ES) has dramatically changed since the advent of disease-targeted therapy (DTT). However, guidelines for ES management, including DTT, have not been established. We aimed to clarify the current incidence, underlying disease, and management of ES in Japan, using a nationwide survey. Methods: A written questionnaire was sent to members of the Japanese Society for Adult Congenital Heart Disease, through which information was obtained from 86 institutions. Results: A total of 251 patients with ES (80.5% cases ≥ 20 years of age) were followed as of February 2012; DTT was performed in 124 (49.4%) patients. Unrepaired simple anatomy was reported as an underlying condition in 165 patients (65.7%). Among patients with ES, 55 (21.9%), 128 (51%), 53 (21.1%), and 12 (4.8%) were classified into functional classes I, II, III, and IV, respectively. DTT was routinely performed at 52 (60.5%) institutions, but there were variations in the DTT therapeutic strategy at these institutions. Combined therapy was more often used than monotherapy; an endothelin receptor antagonist was the most frequently prescribed medication. There were institutional differences regarding heart failure treatment and indications for anticoagulation. Digitalis and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers were widely used, but beta-blockers were infrequently used to manage heart failure. Conclusions: This survey describes the current status, including prevalence and underlying disease, and variations in the practical management of ES in Japan. The results will help in the creation of future guidelines for ES management. © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Introduction Since the advent of pediatric cardiology and cardiac surgery, the outcomes for patients with congenital heart disease (CHD) have significantly improved. Consequently, the majority of patients survive to adulthood [1]. However, some of these patients continue to experience several long-term complications, including pulmonary

∗ Corresponding author at: Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: +81 3 5843 6702; fax: +81 3 5363 3875. E-mail address: [email protected] (T. Inohara).

arterial hypertension (PAH), which is reported in approximately 10% of patients with CHD [2,3]. Eisenmenger syndrome (ES) is defined as the presence of significant PAH in conjunction with CHD and shunt reversal [4]. Compared to idiopathic PAH, patients with ES have better survival prospects [5]; however, the associated morbidity and mortality remain high [6,7]. Recently, the therapeutic strategies for PAH have drastically changed due to the advances of disease-targeted therapy (DTT) involving pulmonary vasodilators, including prostanoids, endothelin receptor antagonists (ERAs), and phosphodiesterase-5 (PDE-5) inhibitors [8–11]. Over the past few years, several studies have shown that DTT is well tolerated and improves clinical outcomes, even in ES patients [12–15]. However, guidelines for the

0914-5087/$ – see front matter © 2013 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jjcc.2013.08.014

T. Inohara et al. / Journal of Cardiology 63 (2014) 286–290

management of ES, including with DTT, have not been established because of insufficient evidence. As a result, the current therapeutic strategies for ES may vary considerably among institutions. In addition, the data in previous reports have been primarily collected from specialized institutions and, therefore, do not accurately reflect the broader clinical situation. In the present study, we aimed to assess both the underlying diseases and the management in patients with ES through a nationwide survey in Japan. The results of this survey will help in the development of future guidelines for ES management. Methods A written questionnaire, designed to define the prevalence of ES and the current clinical management strategies, was sent to 175 institutions (187 departments) to which members of the Japanese Society for Adult Congenital Heart Disease belong. The results were analyzed centrally at St. Luke’s International Hospital, Tokyo, Japan. The questionnaire was designed to record the required information by collecting answers to questions pertaining to the following: 1. Prevalence and characteristics (A) The total numbers of patients with ES who were alive and followed as of February 2012. i. The numbers of adult patients. ii. Types of CHD (simple or complex anatomy [16]). iii. New York Heart Association (NYHA) functional class of each patient. iv. The numbers of patients who received DTT. (B) The total numbers of deaths in patients with ES from April 2000 to February 2012. i. The numbers of sudden deaths, with a description of the details, if possible. ii. The numbers of non-sudden deaths, with a description of the details, if possible. 2. Management (A) Whether or not DTT was performed. i. DTT regimen; monotherapy or combined therapy, drug choice (multiple answers allowed). (B) Whether or not the following drugs were prescribed to treat heart failure: digoxin, diuretics, angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II receptor blockers (ARBs), and beta-blockers. (C) Describe conditions under which anticoagulation therapy (warfarin) was performed. As previously described [4], ES was defined as having the presence of PAH at the systemic level and high pulmonary vascular resistance (>10 units), with reversed or bidirectional shunts through a large unrestrictive atrial or ventricular septal defect (VSD), or aorto-pulmonary communication. If catheterization was not performed, patients who had systemic-level pulmonary artery pressure, estimated by echocardiography, were also included. Data were expressed as the number of specific responses divided by the total numbers of responses (%). If a question was returned with multiple answers, the number of specific responses was divided by the number of individuals who answered the question (%). Results Of the 175 institutions (187 departments) that received questionnaires, responses were received from 86 institutions (49.1%; including 86 departments, 46.0%). The demographic and clinical characteristics of the patients are described in Table 1. In total, 251

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Table 1 Patient characteristics. Total patients, no. Adult, no. (%) Cardiac defects, no. (%) Unrepaired Simple anatomy Complex anatomy Repaired Simple anatomy Complex anatomy NYHA functional class, no. (%) I II III IV Unclear

251 202 (80.5)

165 (65.7) 57 (22.7) 13 (5.2) 14 (5.6) 55 (21.9) 128 (51.0) 53 (21.1) 12 (4.8) 3 (1.2)

NYHA, New York Heart Association.

patients with ES were followed as of February 2012. Among them, 202 patients (80.5%) were adults (aged ≥ 20 years) and the majority (65.7%) had unrepaired simple anatomy. Approximately half of the patients had NYHA functional class II. From April 2000 to February 2012, a total of 86 patients with ES died (Table 2). Although the causes were not identified in 28 individuals, 23 patients died suddenly due to intrapulmonary hemorrhage (n = 7), arrhythmia (n = 3), or unknown causes (n = 13). The remaining 35 patients died due to congestive heart failure (n = 21), pneumonia (n = 6), multiple organ failure (n = 4), cancer (n = 2), infectious endocarditis (n = 1), or pulmonary embolism (n = 1). There were variations in the therapeutic strategies for ES patients (Table 3) among the various institutions. DTT was routinely considered in 52 institutions (60.5%), with DTT being performed in 124 (49.4%) of the patients in this survey. Combined therapy was more likely to be chosen than monotherapy (36 institutions versus 16 institutions, respectively), and ERAs were more frequently prescribed (45 institutions) than oral prostanoids (30 institutions) or PDE-5 inhibitors (35 institutions). Several trends were observed regarding drug choices among the institutions. Bosentan was preferred (44 institutions) over ambrisentan (12 institutions), and most institutions tended to use sildenafil (29 institutions) as opposed to tadalafil (3 institutions) to manage the ES patients. The drugs that were used to treat heart failure included diuretics (56 institutions, 65.1%), ACE-Is or ARBs (40 institutions, 46.5%), and beta-blockers (22 institutions, 25.6%). In more than half of the institutions, anticoagulation therapy was performed only for patients with a history of atrial fibrillation, pulmonary embolism, or mechanical valve implantation.

Table 2 Causes of death in patients with Eisenmenger syndrome. Total patients, no. Unknown causes Identified causes

86 28 58

Sudden death, no. (%) Unclear Intrapulmonary hemorrhage Arrhythmia

23 13 (22.4) 7 (12.1) 3 (5.2)

Non-sudden death, no. (%) Heart failure Pneumonia Multiple organ failure Cancer Infectious endocarditis Pulmonary embolism

35 21 (36.2) 6 (10.3) 4 (6.9) 2 (3.4) 1 (1.7) 1 (1.7)

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Table 3 Therapeutic strategy for Eisenmenger syndrome. Total institute, no.

86

Disease-targeted therapy, no. (%) Yes No No response

52 (60.5) 18 (20.9) 16 (18.6)

Therapeutic options of disease-targeted therapy, no. (%) Monotherapy Beraprost ERA PDE5 inhibitors Combined therapy Beraprost + ERA Beraprost + PDE5 inhibitors ERA + PDE5 inhibitors Beraprost + ERA + PDE5 inhibitors

52 16 3 (5.8) 10 (19.2) 3 (5.8) 36 4 (7.7) 1 (1.9) 9 (17.3) 22 (42.3)

Choice of ERA (multiple answers allowed) Bosentan Ambrisentan

44 (84.6) 12 (23.1)

Choice of PDE5 inhibitor (multiple answers allowed) Sildenafil Tadalafil

29 (55.8) 3 (5.8)

Therapeutic options for heart failure, no. (%) (multiple answers allowed) 56 (65.1) Diuretics ACE-I or ARB 40 (46.5) 35 (40.7) Digoxin 22 (25.6) Beta blocker 22 (25.6) No response Anticoagulation therapy Routine use Only for atrial fibrillation, poulmonary embolism, mechanical valve Never use No response

9 (10.5) 48 (55.8) 11 (12.8) 18 (20.9)

Abbreviations: ERA, endothelin receptor antagonist; PDE5, phosphodiesterase-5; ACE-I, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker.

reported differences in the NYHA functional class distribution of ES patients remains unclear, and the advent of DTT may explain this discrepancy. In 2006, Galie et al. reported a randomized, doubleblind, placebo-controlled study evaluating the effect of bosentan in ES patients; the results indicated that bosentan was well tolerated and improved patient exercise capacity and hemodynamics [12]. Following the publication of these results, DTT has been rapidly and widely adopted as a therapeutic option for ES. Indeed, in this survey, approximately half of the ES patients received DTT. Although the comparison of NYHA functional class between patients with and without DTT is essential to demonstrate the effects of DTT for the improvement of NYHA grade, this study does not include questions related to such issues. Causes of death This survey revealed that 86 ES patients died between April 2000 and February 2012. The prognosis of patients with ES is considerably better than that of patients with idiopathic PAH [5], with reported survival at ages 40, 50, and 60 years being 86%, 74%, and 53%, respectively [19]. Previous studies have reported that most ES patients died from sudden cardiac death, congestive heart failure, hemoptysis, cerebral abscesses, or thromboembolic events [20], and that sudden death was due to a variety of causes, such as massive intrapulmonary hemorrhage or rupture of an aneurysmal pulmonary trunk, rather than arrhythmia [7]. In our survey, sudden deaths accounted for more than 33% of the patient deaths, and these were mostly as a result of intrapulmonary hemorrhage. The causes of non-sudden death were heart failure, pneumonia, multiple organ failure, cancer, infectious endocarditis, and pulmonary embolism, which are consistent with previous reports [20]. In the present survey, deaths related to pregnancy were not reported; however, patients with ES have an extremely high risk of maternal complications during pregnancy and childbirth [21]. Disease-targeted therapy

Discussion Prevalence and incidence Data from the CONCOR registry – a nationwide registry of adult patients with CHDs in the Netherlands – revealed that the prevalence of PAH among the 5970 registered adult patients with CHD was 4.2%, with ES existing in 1% of the total number of registered patients [17]. In 2007, 409,101 adult patients with CHD were estimated to be alive in Japan [18]. Assuming the prevalence of ES in the Netherlands reflects the Japanese situation, approximately 4000 adult ES patients are believed to be alive in Japan. However, in this study, it seems to be difficult to estimate the total number of patients with ES in Japan, because the cohort of this study was collected only from institutions with cardiologists belonging to the Japanese Society of Adult Congenital Heart Disease and was rather limited by the small response rates. A prospective, consecutive, nationwide registry designed to register all cases with ES should be launched to estimate accurately the number of patients with ES. NYHA functional class In this survey, the majority of ES patients were in NYHA functional class II (51%), which is consistent with the results of a recent study in Japan and Korea [19]. In a previous study, conducted in November 2005, a large proportion of the patients were classified in NYHA functional class III [17]. The precise reason for these

Currently, DTT is approved as the therapeutic option for patients with ES. European Society for Cardiology (ESC) guidelines for the diagnosis and treatment of pulmonary hypertension [16], established in 2009, recommend the use of bosentan as a Class I indication for WHO functional class III patients with ES. Other ERAs, PDE-5 inhibitors, and prostanoids are also recommended as Class IIa indications for patients with ES. In this survey, DTT was more frequently performed (60.5% of cases) than in previous studies, reflecting its wide and rapid adoption [6,22], and combined therapy was more likely to be chosen than monotherapy. Furthermore, among the combined therapies, a triplet regimen including ERAs, PDE-5 inhibitors, and beraprost were prominent in our study. Recently, Iversen et al. [23] and D’Alto et al. [24] reported the efficacy and tolerability of combined sildenafil and bosentan therapy. The ESC guidelines for the diagnosis and treatment of pulmonary hypertension recommend combined therapy for refractory cases [16], and the proportion of cases receiving combined therapy is expected to continue to increase as more investigations examining the use of combined therapy for ES patients are reported. ERAs were frequently prescribed for patients involved in this survey, which reflects the amount of evidence supporting the use of ERAs in ES patients [12,13,25–28]. BREATHE-5 was the first randomized, placebo-controlled trial in patients with ES [12], and it demonstrated the long-term efficacy and tolerability of bosentan in an open-label extension study [13]. Ambrisentan, a selective ERA, was prescribed at 12 institutions (23.1%) in the current survey. This

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drug was assessed for its safety and efficacy in a single cohort study in ES patients, and further investigations are required [28]. PDE-5 inhibitors comprise an alternative treatment option for ES patients, and the evidence supporting their favorable effects has been growing [14,15,29–31]. In our survey, PDE-5 inhibitors were prescribed at 35 institutions (60.3%), and sildenafil accounted for a substantial proportion of those prescriptions. There is limited evidence for the effects of tadalafil [14,31], and only 2 institutions prescribed this PGE-5 inhibitor in this survey. Previous reports have suggested that beraprost, a prostaglandin I2 analog, might also provide beneficial effects during the early phase of treatment in patients with ES [32], but also that this favorable effect becomes attenuated over time [33]. In Western countries, beraprost is currently prescribed only in limited cases, according to the results of previous studies, whereas up to 30 institutions (57.7%) prescribed it in this survey, which may be attributed to its cost-effectiveness and safety. The effectiveness of DTT for pulmonary artery hypertension has been established [16], and this concept is endorsed for the treatment for ES, which is reflected in this study. However, this study does not provide sufficient data to emphasize the current concept of DTT, established for treatment of PAH, because of the study design; therefore, further studies are needed.

Heart failure treatment strategy There have only been few randomized controlled trials of any medications for heart failure in patients with CHD. Shaddy et al. reported a randomized controlled trial examining the effects of carvedilol for children and adolescents with heart failure, including those with CHD [34]. Their trial concluded that carvedilol did not improve the clinical outcomes, contradicting the results of previous studies conducted in adult patients with heart failure [35–37]. However, recently, a few reports described the beneficial aspects of beta-blockers, including carvedilol, for patients with CHD or right ventricular systemic dysfunction [38,39]. In a reflection of these backgrounds, one tenth of institutes routinely prescribed betablocker for heart failure treatment accompanied with CHD in this study. Further investigations regarding the efficacy of beta-blockers for treating heart failure accompanied with ES are expected.

Anticoagulation therapy Although the ESC guideline has recommended oral anticoagulant treatment for patients with PAH [24], the value of anticoagulation in ES patients has not been established. Indeed, ES has been associated with both bleeding and clotting tendencies [7,20,40,41]. These conflicting observations make developing recommendations for the use of anitcoagulants in ES patients difficult. Recently, a retrospective cohort study revealed that anticoagulation did not affect long-term survival in ES patients [42], and that the indications should be carefully considered. In our survey, anticoagulation was performed only for selected cases at most institutions. However, a small minority of institutions routinely applied anticoagulation therapy. Such strategic variations among institutions should be discussed, and the best practice should be adopted broadly. Recently in Japan, new anticoagulation drugs, such as dabigatran, rivaroxaban, and apixaban, have been approved. However, because the indication for the use of these new anticoagulants is restricted to atrial fibrillation caused by non-valvular heart disease and the period between the approval of dabigatran, the first alternative to warfarin, and the start of this study was short, we did not focus on these new anticoagulants in this survey. Further studies

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are needed to evaluate the efficacy and safety of new anticoagulation drugs for ES patients. Study limitations Our survey has several limitations. First, written questionnaires were sent only to the institutions with cardiologists belonging to the Japanese Society of Adult Congenital Heart Disease. In Japan, many additional institutions provide medical care for ES patients, and these institutions were not considered in this survey. Second, the institutions that responded to the questionnaires are believed to be representative of the major Japanese medical facilities that manage adult CHD; however, there is a possibility that the level of response introduced a positive bias into the study. Third, outcome measures for the diagnosis and treatment of ES were not assessed. Finally, the diagnosis of ES was not validated, and whether the patients whose pulmonary vascular resistance had already improved with DTT were included as ES remains unclear in this study; therefore, the reported incidence of ES may not reflect the real number of cases. Conclusion This is the first nationwide survey examining the current status and management of ES in Japan. This survey revealed that DTT is widely used and that there are variations in the therapeutic strategies for patients with ES employed by the different institutions. The results will help in the creation of future guidelines for ES management. Funding sources This study was supported by a grant from the Advanced Clinical Research Organization. Disclosures None declared. Acknowledgments We gratefully acknowledge the assistance of the 86 institutions, which are listed in the Supplementary File. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jjcc.2013.08.014. References [1] Moons P, Bovijn L, Budts W, Belmans A, Gewillig M. Temporal trends in survival to adulthood among patients born with congenital heart disease from 1970 to 1992 in Belgium. Circulation 2010;122:2264–72. [2] Kidd L, Driscoll DJ, Gersony WM, Hayes CJ, Keane JF, O’Fallon WM, Pieroni DR, Wolfe RR, Weidman WH. Second natural history study of congenital heart defects. Results of treatment of patients with ventricular septal defects. Circulation 1993;87(Suppl.):I38–51. [3] Steele PM, Fuster V, Cohen M, Ritter DG, McGoon DC. Isolated atrial septal defect with pulmonary vascular obstructive disease – long-term follow-up and prediction of outcome after surgical correction. Circulation 1987;76:1037–42. [4] Wood P. The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. Br Med J 1958;2:755–62. [5] Hopkins WE, Ochoa LL, Richardson GW, Trulock EP. Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant 1996;15:100–5. [6] Diller GP, Dimopoulos K, Broberg CS, Kaya MG, Naghotra US, Uebing A, Harries C, Goktekin O, Gibbs JS, Gatzoulis MA. Presentation, survival prospects, and predictors of death in Eisenmenger syndrome: a combined retrospective and case–control study. Eur Heart J 2006;27:1737–42.

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