Pulmonary vasodilator therapy as treatment for patients with a Fontan circulation: the Emperor’s new clothes?

Abstract

With great interest we read the recent article by Wang et al. in Pulmonary Circulation presenting a meta-analysis on the efficacy and safety of pulmonary vasodilator therapy in patients with a Fontan circulation. 1 We commend the authors with this thorough attempt to provide an overview of the available evidence on this important and controversial topic. The authors report that they have performed a metaanalysis of randomized controlled trials (RCTs) and conclude that pulmonary vasodilator therapy, although not reducing mortality, improves peak oxygen consumption (pVO 2), hemodynamics, and 6-min walking distance (6MWD) and reduces NYHA functional class statistically significantly based on nine studies. After thorough assessment of the manuscript and considering the increased interest for the use of pulmonary vasodilator therapy in Fontan patients, we feel the necessity to express our concerns regarding the claims and conclusions drawn by the authors. Meta-analyses can be a valuable tool to assess systematically available information from different studies in order to derive conclusions from the total body of research. However, it cannot provide evidence that is not there. The current meta-analysis includes extremely heterogeneous data from a limited number of studies with significant clinical and methodological diversity. When substantial heterogeneity exists, pooling data from multiple trials and presenting a single summary estimate can be misleading and should be avoided. 2 There are several important points to take into consideration when interpreting this meta-analysis. First, concerning inclusion criteria; two of the included studies are not RCTs (one retrospective design and one prospective design with a historical cohort control group) and thus in fact do not fulfill the authors' inclusion criteria of RCT-only studies. 3,4 Without these two studies there is only one RCT reporting on mean pulmonary artery pressure (mPAP) 5 and only RCT data from one medical center on mortality, 5,6 making a metaanalysis on hemodynamics and mortality a futile attempt.

2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

“…While some series have reported promising results, there have been cases where therapies were not tolerated [581]. Similarly, using PAH therapies in Fontan circulation has yielded conflicting results, and results of further studies are awaited [582][583][584].…”

2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

“…581 Similarly, using PAH therapies in Fontan circulation has yielded conflicting results, and results of further studies are awaited. [582][583][584] Heart-lung transplantation or LTx with heart surgery is an option in highly selected cases not responsive to medical treatment; however, it is limited by organ availability and lesion complexity. Mortality is high during the first year after surgery, especially after heart-lung transplantation, but remains relatively low thereafter.…”

Pulmonary Vascular Disease in the Single-Ventricle Patient: Is it Really Pulmonary Hypertension and if So, How and When Should We Treat it?

“…raises concerns about the heterogeneity of the populations previously studied, limited knowledge about pulmonary vascular remodeling in the Fontan circulation, and current lack of randomized controlled trials, especially late after the Fontan operation involving more than a single dose of therapy. 29 Overall, there are several promising studies, particularly in subgroups of symptomatic patients, that suggest some patients with Fontan circulation may benefit from pulmonary vasodilator therapy. At this time, however, there is no evidence to routinely recommend pulmonary vasodilator therapy for all Fontan patients.…”