Disease targeting therapies in patients with Eisenmenger syndrome: Response to treatment and long-term efficiency☆
Introduction
Advances in paediatric cardiology and cardiac surgery have transformed the outcome of children born with congenital heart defects over the past 6 decades. As a consequence, the vast majority of patients now survive to adulthood [1]. Only a minority of patients, however, can be regarded as cured. In most patients long-term complications remain, with pulmonary arterial hypertension (PAH) representing one of the common problems [2], [3], [4]. Approximately 5–10% of patients develop PAH of variable severity which impacts on quality of life, morbidity and mortality [5], [6], [7], [8]. The extreme manifestation of PAH in this setting—Eisenmenger syndrome—has become the epitome of PAH associated with congenital heart disease [9]. It is estimated that up to 4% of contemporary adult congenital heart patients under tertiary follow-up in Europe and North America have Eisenmenger syndrome [10]. A greater proportion of patients may be afflicted by Eisenmenger syndrome in developing countries [11].
Until a decade ago, management options for patients with Eisenmenger physiology have been limited to palliative measures and lung or heart-lung transplant in a highly selected subgroup. Recently, safe and effective drug therapy has become available for the treatment of PAH. This includes endothelin receptor antagonists, phosphodiesterase-5 inhibitors and prostanoids [12]. The former two classes can be administered orally and are therefore attractive options in patients with Eisenmenger syndrome. Over the last decade a number of studies—including a randomised placebo-controlled double-blinded trial—have demonstrated that treatment with disease targeting therapies (DTT) is safe in the Eisenmenger setting and has the potential to improve exercise capacity and symptoms, at least short term [13]. Given the superior survival prospects of Eisenmenger patients compared to patients with idiopathic or other forms of PAH and the considerable costs of therapy, the long term effects of DTT are of clear interest [14], [15]. Data on the long-term impact of disease targeting therapies on symptoms, exercise capacity and oxygen saturation in Eisenmenger patients is limited, however at present.
In this study we set out to investigate what proportion of Eisenmenger patients responds to DTT, assess the time course of symptomatic improvement and evaluate the longer-term efficacy of drug therapies.
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Patients and methods
All adult patients with Eisenmenger syndrome treated with DTT at our institution were identified from a computerised audit database and were included in this retrospective analysis. Medical records were reviewed and underlying demographics, as well as clinical characteristics (including functional class [FC] and 6-minute walk test distance [6MWTd]), were recorded.
The diagnosis of Eisenmenger syndrome had been ascertained by echocardiography, cardiovascular magnetic resonance imaging, or cardiac
Results
Between 02/2002 and 11/2010, 79 Eisenmenger patients were commenced on DTT and were included in the current study. Demographic and clinical information for the study population is presented in Table 1.
The median follow-up period was 3.3 years (IQR 1.6 to 4.8 years, with a minimum of 4 months and a maximum of 8.9 years). During this period 2 patients died despite being treated with DTT (both on single therapy with Bosentan). As shown in Fig. 1, four patients required switching to a different drug
Discussion
The current study shows that DTT improve symptoms and exercise capacity in patients with Eisenmenger physiology and this effect may be maintained up to 8 years from initiation of treatment using contemporary single or combination therapy. The vast majority of Eisenmenger patients responded to DTT either by improving 6MWTd, FC or both. In addition, increasing O2-saturations, especially during exercise, were observed.
Since the publication of the first 2 prospective, open-label studies suggesting a
Conclusions
Long-term DTT is safe and improves objective exercise capacity and subjective symptoms. The vast majority of Eisenmenger patients responded with an improved FC or 6MWTd early after initiation of DTT and this effect was—on average—maintained longer-term. With time, approximately 1 in 5 patients, however, required escalation of DTT due to symptomatic deterioration and this was associated with an afresh improvement in 6MWTd. In addition, DTT improved O2-saturation especially in patients with low
Acknowledgements
The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
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Disclosures: Dr Diller has received unrestricted educational grants from Actelion, UK and has served on the advisory board of Actelion, Germany. Dr Alonso-Gonzales has served on the advisory board of Lilly, Spain. Dr. Dimopoulos has served on the advisory board of Actelion Europe. Dr SJ Wort has received educational grants from Actelion and has served on the advisory boards of Pfizer, Bayer and Eli-Lily. Professor Gatzoulis has served on the advisory board of Actelion, Pfizer, and GlaxoSmithKline and has received unrestricted educational grants from Actelion and Pfizer, UK.
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GPD and RAG contributed equally to this work.