Response by Kempny et al to Letter Regarding Article, “Predictors of Death in Contemporary Adult Patients With Eisenmenger Syndrome: A Multicenter Study”
Authors: Aleksander Kempny, Cristel Sørensen Hjortshøj, Wei Li, Annette Schophuus Jensen, Lars Søndergaard, Gerhard-Paul Diller, Konstantinos Dimopoulos, Stephen J. Wort, Michael A. Gatzoulis
Journal: Circulation (2017)

We thank Ferrero et al for their interest in our recent publication in Circulation. 1 We aimed in this study to assess mortality and management strategies in contemporary patients with Eisenmenger syndrome (ES).Although the incidence and prevalence of ES seem to decrease in developed countries, it remains worldwide a common complication of congenital heart disease. 2,3There has been considerable progress in the management of ES over the past 1 to 2 decades.Routine phlebotomies, for example, often resulting in iron deficiency, microcytosis, and inappropriately low hemoglobin levels, have been abandoned. 4There is increased awareness of the risks associated with even minor surgery and pregnancy; as a result, fewer patients with ES die of periprocedural complications. 5Last, targeted therapies for pulmonary hypertension have been introduced and helped by improving pulmonary hemodynamics, exercise capacity, quality of life, and seemingly survival.Despite this progress, mortality remains high, as demonstrated in our study, although survival prospects vary significantly between patients.Some patients with ES die in their childhood, whereas others survive into late adulthood.Prognostication in these patients is therefore pivotal and may help in informing patients, optimizing conventional therapy, and, crucially, identifying patients who may benefit from heart and lung or lung transplantation.We elected to use a Cox proportional hazards regression model in our study to test the association of various parameters with mortality.This is currently the most widely used and accepted approach for mortality risk stratification.We have carefully assessed the correlation of parameters tested in the multivariable model to avoid multicollinearity.Although ES is an orphan disease, the multicenter effort enabled analysis of a large cohort of 1098 patients; 278 of them died during the follow-up.We have included in the multivariable model only the parameters available in the vast majority of patients to maintain the ratio of events to parameters at >10 and to avoid overfitting.However, we agree with Ferrero et al that our prognostic model would benefit from external validation.With this in mind, we are currently working on a further study testing our statistical model in a different patient cohort to provide absolute mortality risk estimates in this challenging population.Further progress in mortality risk stratification in patients with congenital heart disease will require multicenter collaboration and analysis of big data, offering sufficient quality and granularity.Although the multivariable model presented in our publication seems promising, in view of future analyses, the results of the univariable analysis require particular attention.This analysis identified a number of parameters significantly associated with mortality that were, however, not available in a significant subset of patients and therefore were not included into the multivariable model.These included 6-minute walk test distance, brain natriuretic peptide, serum albumin, C-reactive protein, and tricuspid plane systolic excursion on echocardiography.We propose that these simple parameters should be incorporated into the routine, periodic assessment of patients with ES both to Response by Kempny et al to Letter