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Survival in Eisenmenger syndrome: a paradigm shift in outcomes research for adult congenital heart disease? Ami B Bhatt In 1958, Paul Wood defined Eisenmenger syndrome as ‘Pulmonary hypertension due to a high pulmonary vascular resistance with reversed or bidirectional shunt at aortopulmonary, ventricular, or atrial level.’ He went on to state ‘As life advances, usually between the ages of 20 and 30, thrombo-obstructive lesions develop in the larger pulmonary arteries which increase the resistance considerably and herald the beginning of the downhill course.’1 As the field of congenital heart disease (CHD) progressed, and individuals lived beyond the second and third decades of life, a concept was born which has been clung to by physicians and patients alike … Eisenmenger syndrome portends a better prognosis than other causes of pulmonary hypertension, and less is more. In the article, ‘Survival Prospects of Treatment Naive Eisenmenger Patients—A Systematic Review of the Literature and Report of Own Experience’,2 our colleagues, including those from the Brompton, offer a modern-day treatise on the untreated Eisenmenger patient and a new lens through which we should assess this fatal disease. Eisenmenger syndrome is a severe form of pulmonary arterial hypertension and arises in CHD with a systemic-to-pulmonary shunt. Individuals with Eisenmenger syndrome have multisystem involvement as a result of chronic hypoxaemia with renal and liver dysfunction, coagulation disorders, neurologic complications, heart failure, arrhythmias, and often sudden and premature death. Diller et al challenged the premise that high levels of pulmonary vascular resistance, nearly lifelong cyanosis, and multisystem organ failure portend a better prognosis. They also astutely noted that the Eisenmenger population’s outcomes have not considerably improved since the 1960s. During much of this time, treatment was symptom guided (for reduced exercise tolerance, increasing cyanosis or heart

Correspondence to Dr Ami B Bhatt, Department of Cardiology, Massachusetts General Hospital, Adult Congenital Heart Disease Program, Boston, MA 02114, USA; [email protected] 1308

failure presentation), and stable ‘asymptomatic’ patients were not treated. Lung or heart-lung transplantation remained a last resort for the hospital-bound individual. With the advent of selective pulmonary arterial vasodilators, an improved quality of life, delay of deterioration and prolonged survival are now realistic goals in Eisenmenger syndrome.3 The study by Diller et al raises several important and timely topics in adult CHD (ACHD).

‘BIG DATA’—A NEW DIRECTION FOR ACHD RESEARCH Dr Diller and colleagues take a new approach to assessing outcome in Eisenmenger syndrome, one which may benefit the ACHD population as a whole. The authors performed a systematic review of the literature and meta-analysis of existing survival studies in Eisenmenger syndrome to re-evaluate survival prospects while correcting for immortal time bias. Immortal time in epidemiology refers to a period of follow-up time during which death cannot occur. The authors therefore implemented methods for generating survival curves that account for left truncation in order to assess survival in the Eisenmenger population without immortal time bias. Almost by definition, the vast majority of Eisenmenger individuals included in published studies were not observed beginning at birth or at the time of shunt reversal. These individuals had survived to an age when they presented for clinical follow-up and could be included in research studies. As a result, without accounting for the years prior to presentation, the Eisenmenger syndrome studies to date carry a more favourable outlook than truly exists for this population. Diller et al demonstrate that immortal time (or survivor) bias significantly affects the evaluation of outcomes in Eisenmenger syndrome, and may need to be considered in ACHD outcomes research. Despite the increased focus on multicenter research in rare diseases, the power of ‘big data’4 is one worth investigating for ACHD. While awaiting prospective studies in a heterogenous group of rare disorders, the pace of scientific advancement often makes the randomised Bhatt AB. Heart September 2014 Vol 100 No 17

controlled trial result less applicable by the time it is published. Many centres now have registries and prospective databases resulting in detailed prospective cohort studies. Administrative datasets and electronic medical records are also designed to accommodate research efforts. The application of a ‘big data’ approach, with appropriate use of propensity analysis and time-dependent survival analysis, may become a cornerstone of ACHD outcomes research over time. In the growing and ageing population of ACHD where observation, clinical acumen, and longitudinal care provision has formed the basis of most of the guideline recommendations,5 it is important that research to support long-term management recommendations is emphasised as the next guidelines are released. The small cohort study, a key to scientific progress in ACHD, must be supplemented with larger studies. Meta-analyses and intelligent use of statistics, without ‘gaming the system’, may aid in reinterpreting trends and data as Diller et al have demonstrated. Certainly, this study has opened our eyes to a bias that may exist in ACHD: have we favourably biased outcome assessment in the field as a whole? Certainly for studies which follow individuals from birth to adulthood or have matched populations, this concern is abated. However, the high rate of loss to follow-up and late arrival to care in ACHD inherently selects a population that was able to survive until presentation. In a heterogenous population such as adults with CHD, a blanket statement regarding the approach to survival analysis cannot be made, but the implications are clear: we have an opportunity to assess and reassess long-term outcomes in our population with systematic rigour.

THE IMPORTANCE OF INFRASTRUCTURE IN ACHD This study has broader implications for the infrastructure necessary to accurately predict, and ultimately improve, outcomes in ACHD. Early intervention to avoid the development of Eisenmenger syndrome requires first, identification of the individuals with CHD. The US Centers for Disease Control and Prevention recently awarded grants for population-based surveillance of CHDs among adolescents and adults to assess the prevalence of CHD and ideally improve access to care. Even in countries where access is less of an issue, early identification and referral to an ACHD centre requires infrastructure and ease of communication. With modern technology, some ACHD programmes use

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Editorial telemedicine consultations with front-line caregivers to encourage this transfer of care. For those who have already developed Eisenmenger syndrome, the institution of pulmonary arterial vasodilators improves quality of life and may provide a survival benefit. Education infrastructure for the primary caregiver, the local cardiologist and pulmonologist, and discussions among the ACHD/PAH experts to ensure understanding of the role of early vasodilator therapy is essential. Perhaps most importantly, it falls on the CHD field as a whole to educate patients and families to actively participate in lifelong care.

UNDER-RECOGNITION OF PULMONARY HYPERTENSION IN ACHD Eisenmenger syndrome represents the tip of the pulmonary hypertension iceberg in CHD.6 Nearly half the ACHD population has some level of elevated systolic

pulmonary arterial pressure.7 Despite earlier interventional or operative therapy, a considerable number of CHD patients still develop pulmonary arterial hypertension (PAH).8 The timing and indications for treatment continue to be debated. While structural contributors often need to be addressed first, progressive subpulmonic ventricular decline can occur with even low consistent levels of elevated pulmonary vascular resistance (PVR). Imaging of right heart function needs to be standard in the care of these individuals, and should be considered in the algorithm for pulmonary arterial vasodilator treatment. Unfortunately, heart failure admissions, along with arrhythmias, comprise a majority of inpatient admissions for individuals with ACHD and use considerable resources. Early and appropriate treatment of elevated PVR in ACHD without Eisenmenger syndrome may reduce morbidity and

improve quality of life while reducing healthcare costs, and may further improve the cost effectiveness of the pulmonary arterial vasodilators in the ACHD population. However, with increased survival, whether of Eisenmenger or ACHD/PAH patients, demand for these expensive medications may incur medication costs as well. The ideal would be early identification of PAH in ACHD, and algorithms to avoid elevations in PVR long before medical treatment is even needed. This requires identification of at-risk individuals (many individuals with ACHD), informed guidelines for interval assessment for PAH, infrastructure for referral to specialised centres to intervene when necessary, and mechanisms to follow these patients locally once treatment is initiated to avoid overuse of tertiary hospital resources (figure 1). Overall, Diller et al have demonstrated that Eisenmenger syndrome may have a

Figure 1 Algorithm for ACHD/PAH or Eisenmenger Life-Long Care. Red shading denotes point of potential concern; green shading highlights decision making which should occur in concert with an ACHD centre; blue shading designates testing and procedures when indicated. ACHD, Adult Congenital Heart Disease; PAH, pulmonary arterial hypertension. Bhatt AB. Heart September 2014 Vol 100 No 17


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Editorial worse survival prognosis than previously thought, an idea first proposed by their predecessor Paul Wood over 40 years ago. They have introduced the importance of accounting for ‘survivorship’ in ACHD research and demonstrated the modern day use of ‘big data’ in a rare population. As this population ages, the old standard of clinical experience and consensus opinion in how to manage select populations will increasingly be challenged by detailed and complex large volume statistical analyses. Our goal will be to find the correct balance for ACHD outcomes research. The authors indirectly highlight the importance of infrastructure for lifelong ACHD care and outcomes assessment. In doing this, they motivate us to create a paradigm for systematic longitudinal ACHD care and a research process which is dynamic with the times, as we enter the next phase of progress in this growing field of cardiology.


Competing interests None. Patient consent Obtained.


Provenance and peer review Commissioned; internally peer reviewed. 4 5

To cite Bhatt AB. Heart 2014;100:1308–1310.



Heart 2014;100:1308–1310. doi:10.1136/heartjnl-2014-306211




Wood P. The Eisenmenger Syndrome or pulmonary hypertension with reversed central shunt. BMJ 1958;2:755–62. Diller GP, Kempny A, Inuzuka R, et al. Survival prospects of treatment Naïve Eisenmenger patients: a


systematic review of the literature and report of own experience. Heart 2014;100:1366–72. Dimopoulos K, Inuzuka R, Goletto S, et al. Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension. Circulation 2010;121:20–5. Sebastian S. Learning from Big Health Care Data. N Engl J Med 2014;370:2161–3. Warnes CA, Williams RG, Bashore TM, et al. ACC/ AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: Executive Summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines for the management of adults with congenital heart disease). Circulation 2008;118:2395–451. Diller GP, Gatzoulis MA. Pulmonary vascular disease in adults with congenital heart disease. Circulation 2007;115:1039–50. Annelieke CMJ van Riel, A Zomer, Mark Schuuring, et al. Epidemiology of Pulmonary Arterial Hypertension in Congenital Heart Disease; Nationwide Prevalence and Impact on Socioeconomic Status. J Am Coll Cardiol 2012;59(13s1):E1616. Engelfriet PM, Duffels MG, Möller T, et al. Pulmonary arterial hypertension in adults born with a heart septal defect: the Euro Heart Survey on adult congenital heart disease. Heart 2007;93:682–7.

Bhatt AB. Heart September 2014 Vol 100 No 17

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Survival in Eisenmenger syndrome: a paradigm shift in outcomes research for adult congenital heart disease? Ami B Bhatt Heart 2014 100: 1308-1310

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Survival in Eisenmenger syndrome: a paradigm shift in outcomes research for adult congenital heart disease?

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