Elsevier

International Journal of Cardiology

Volume 299, 15 January 2020, Pages 131-135
International Journal of Cardiology

A single-centre, placebo-controlled, double-blind randomised cross-over study of nebulised iloprost in patients with Eisenmenger syndrome: A pilot study

https://doi.org/10.1016/j.ijcard.2019.07.004Get rights and content

Highlights

  • Eisenmenger syndrome (ES) is an important subgroup of pulmonary hypertension complicating congenital heart disease.

  • Advanced therapies have improved the lives of patients with pulmonary arterial hypertension (PAH)

  • Advanced therapy use in ES is derived from non-controlled data in ES and controlled data on other forms of PAH

  • Iloprost, a potent vasodilator, did not improve 6 min walk distance in patients with ES

  • Iloprost was safe to use in patients with ES.

Abstract

Background

Pulmonary arterial hypertension (PAH), is a rare and progressive disease with a high morbidity and mortality. Prostanoid pulmonary vasodilators are the most effective treatment for idiopathic and connective tissue associated PAH. Nonetheless, data examining their safety and efficacy in patients with Eisenmenger syndrome the most severe form of PAH, that is, related to cyanotic congenital heart disease (CHD-PAH) remains limited.

Aim

To evaluate safety and the clinical efficacy of nebulised iloprost in patients with Eisenmenger syndrome who are on maximum background oral PAH therapy.

Methods

This pilot study was a randomised, double-blind, placebo-controlled, cross-over study. Patients were randomised to receive nebulised placebo or iloprost for 12 weeks and were then crossed over, with a 7–14-day washout. The primary endpoint was a change in 6-minute walk distance (6MWD).

Results

Sixteen patients (11 females, aged 47.3 ± 9.8 year) were recruited, twelve completed the study. All were in WHO-FC III, with a resting oxygen saturation of 84 [81–87] % and a median 6MWD of 290 [260–300] m. There was no significant difference in the primary endpoint between nebulised iloprost (0[−4–9]m) and placebo (10 [−15–51]m), p = 0.58. There were no safety concerns with nebulised iloprost.

Conclusions

Our pilot study provides preliminary evidence that the addition of nebulised iloprost to maximum oral PAH therapy did not improve the primary endpoint of 6MWD. Nebulised iloprost was well tolerated with no significant safety concerns in CHD-PAH.

Introduction

Pulmonary arterial hypertension (PAH) describes a heterogeneous group of conditions sharing similar pulmonary arterial vasculopathy, resulting in right heart failure and premature death. PAH may be idiopathic, heritable, related to exposure to drugs or toxins, or associated with conditions such as connective tissue diseases or congenital heart disease (CHD). The prevalence of PH in patients with CHD is approximately 5–10%, which is likely to rise as patients with more complex defects survive to adulthood [1]. Eisenmenger syndrome (ES) is the most severe form of CHD-PAH, a multisystem disorder characterised by chronic hypoxemia due to a persistent or unrepaired defect, culminating in a right -to left shunt. Treatment of ES with targeted PAH therapy has resulted in improvements in exercise tolerance, quality of life (QoL) and mortality [2,3]. However, controlled data in ES is limited compared to other PAH aetiologies. Thus far, five randomised control trials, testing the use of phosphodiesterase type 5 inhibitors (PDE-5i) or endothelin receptor antagonists (ERAs), as a single or combined therapy, have been completed in patients with ES [[4], [5], [6], [7], [8]]. The latest, the MAESTRO study, testing macitentan, a novel dual receptor ERA, was safe and well tolerated; however, the primary endpoint, namely 6MWD, was no different in the macitentan vs the placebo arm [8]. It is common practice to treat patients with CHD-PAH, including ES patients, with combination oral therapy (endothelin receptor antagonist (ERA) and a phosphodiesterase type 5 inhibitor (PDE-5i)). However, the question whether to consider triple therapy, with the addition of a prostanoid, the third line and most effective PAH therapy, is limited to non-randomised control data.

The aim of our study was to test the hypothesis that the inhaled prostanoid, iloprost, would be safe and provide additional benefit in patients with ES, who had inadequate control on oral combination therapy.

Section snippets

Study design and patient selection

This was a single-centre, randomised, double-blinded, placebo-controlled (1,1, iloprost: placebo), cross-over study to evaluate the safety and efficacy of nebulised iloprost in patients with ES, on maximal tolerated oral PAH therapy. Study participants were recruited between December 2014 and November 2015, provided they were over 18 years of age, in WHO functional class III or more, with documented resting oxygen saturations of <90% and a 6-minute walk distance (6MWD) of <400 m, or a

Results

A total of 16 patients were recruited and followed up between December 2014 to March 2018. During the study, 2 patients were withdrawn following documented serious adverse events (SAEs; placebo =2). A further 2 patients were withdrawn, one following a serious adverse reaction in one (SAR; placebo = 1) and the other for failing screening at their baseline visit. In total, 15 patients were randomised at baseline visit. Overall, 12 patients completed the main study and 5 patients continued into

Discussion

In our cross-over placebo-controlled randomised study, patients with ES did not experience a significant improvement in exercise capacity at 12 weeks with the addition of nebulised iloprost on a background of maximally tolerated oral PAH therapy. Moreover, no significant difference was seen in resting oxygen saturations, BNP, quality of life, functional class or major echocardiographic parameters. Whilst no significant safety concerns arose with the use of nebulised iloprost, the role of this

Conclusion

This pilot randomised, double-blind, placebo controlled, cross-over study provides preliminary evidence that the addition of nebulised iloprost to maximum oral PAH therapy did not improve exercise capacity, functional class, BNP or echocardiographic parameters in ES. Moreover, there were no safety concerns with the use of nebulised iloprost in our population. Considering the limitations of small sample size and population heterogeneity, further multi-centre trials, utilising contemporary

Acknowledgements

This study was kindly supported by a research grant from Bayer PLC. Bayer PLC supplied the iloprost trometamol and placebo used in this study.

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