Pulmonary vasodilators and exercise in Fontan circulation: a systematic review and meta-analysis

Objective In Fontan circulation, pulmonary arterial hypertension (PAH)-targeted therapies could improve the patients’ exercise capacity. This study aimed to investigate the effects of PAH agents on different exercise parameters in stable Fontan patients by synthesising evidence of randomised controlled trials (RCTs). Methods A systematic search of PubMed, Cochrane Central Register of Controlled Trials and Web of Science databases, as well as of ClinicalTrials.gov, was performed. Primary outcomes were specific cardiopulmonary exercise test parameters: peak oxygen uptake (peak VO 2 ), peak heart rate (peak HR), the minute ventilation/produced carbon dioxide (VE/VCO 2 ) slope and the oxygen uptake, both measured at the anaerobic threshold (VO 2 @AT). Results Five RCTs were included in the analysis including 573 Fontan patients (mean age 21.2 years, 60% male). PAH-targeted therapies did not affect peak VO 2 (mean difference (MD) 0.72, 95% CI −0.25 to 1.70) or peak HR (MD −0.67, 95% CI −3.81 to 2.47), but resulted in a small, significant improvement in VO 2 @AT (standardised MD 0.24, 95% CI 0.02 to 0.47). VE/VCO 2 slope at the anaerobic threshold was also reduced (MD −1.13, 95% CI −2.25 to −0.01). Conclusions Although PAH-targeted therapies did not affect exercise parameters at maximal effort, they induced slight improvements in indices of submaximal effort, measured at the anaerobic threshold. Pharmacological improvement of submaximal exercise seems to be a more suitable indicator of Fontan individuals’ exercise capacity. Larger RCTs, recruiting specific subpopulations and focusing also on the anaerobic threshold, are warranted to draw more robust conclusions. PROSPERO registration number CRD42022306674.