Eisenmenger syndrome (ES) is a complex clinical condition characterized by severe pulmonary arterial hypertension (PAH) secondary to congenital heart disease (CHD) [10, 11]. Although previous clinical trials have shown that PAH targeted drug therapy can improve exercise tolerance and corresponding vascular remodeling in ES patients to a certain extent, the current drug selection for such patients still mainly depends on clinical treatment. A total of 13 studies were included in this meta-analysis, covering 393 patients with Eisenmenger syndrome (ES). Among these patients, those with ventricular septal defect (VSD) accounted for more than 50%. This high prevalence may be related to the persistent high blood flow in the pulmonary circulation associated with VSD. Patients with ES who received targeted drug therapy (including ERAs (54.55%), PDE5i (18.18%) and Prostanoids (27.27%) could improve cardiac function to some extent, and the risk of death and clinical deterioration rate were relatively low, and adverse reactions were mild. It is suggested that targeted drugs are safe and effective clinical prescription for ES [12]. The study found that targeted drug therapy could improve the clinical efficacy and hemodynamics of ES patients in the early stage, but the effect gradually declined in the later stage and individual differences existed [13]. Therefore, the clinical efficacy of ES patients with different characteristics can be evaluated separately.

In the included studies, data on mortality rates and incidence of clinical deterioration events were limited. Only a few studies reported these outcomes, and the overall mortality rate was low, with no significant differences observed between treatment groups. The incidence of clinical deterioration events, such as dyspnea, syncope, and acute heart failure, was also low, suggesting that targeted therapies are generally safe and well-tolerated in ES patients. However, due to the limited data, it is difficult to draw definitive conclusions about the long-term impact of these therapies on mortality and clinical deterioration. Future studies with longer follow-up periods and larger sample sizes are needed to better assess these outcomes.

The meta-analysis and subgroup analysis of the short-term and long-term clinical outcomes of targeted drug therapy for ES showed that the three targeted drug therapies could effectively improve the clinical outcomes of ES patients, including the increase of 6MWD level and the improvement of cardiac function. Among them, prostacyclin was more effective in increasing 6MWD by 132.35 m (95% CI: 14.82-249.89, P = 0.03) and improving cardiac function [MD= -1.26, 95% CI: (-1.66, -0.86), P < 0.0001]. ERAs and PDE5i analogues showed similar improvements. ERAs improved 6MWD by approximately 41.60 m (95% CI: 21.76–61.44, P < 0.0001, I2 = 32%) and improved cardiac function by -0.54 [95% CI: (-0.96, -0.11), P = 0.01]. PDE5i improved 6MWD by approximately 52.33 m (95% CI: 29.16–75.50, P < 0.0001, I2 = 0) and improved cardiac function [MD=-0.38, 95% CI: (-0.64, -0.13), P = 0.003]. Also, different treatment durations had a significant effect on the exercise tolerance effect in patients. Subgroup analyses resulted that short-term and long-term treatments with targeted drugs increased 6MWD levels by approximately 64.33 m (P = 0.0003) and 51.72 m (P = 0.0002), respectively. The improvement effect of long-term treatment on cardiac function [MD = -0.79, 95% CI: (-1.02, -0.56), P < 0.0001] was better than that of short-term treatment (MD = -0.56, 95% CI: (-0.88, -0.24), P = 0.0006).

Patients with comorbid DS are an important subgroup of the ES population [14]. This population has a higher risk of hypoxemia and cardiac insufficiency than the non-DS population [15]. There is a lack of specific treatment for these patients [16]. Bosentan, a widely used non-selective ERA, has been shown to improve exercise tolerance and clinical symptoms in patients with ES, as well as to delay and improve pulmonary vascular remodeling to a certain extent, allowing patients to have access to heart transplantation [17]. In the present study, the proportion of ES patients with definite combined DS was about 1%. Five studies included ES-DS patients and evaluated their exercise tolerance before and after treatment, and the results showed that targeted drugs significantly increased 6MWD levels in ES-DS patients (MD = 37.33, 95% CI: 15.32–59.34, P = 0.0009). Three studies included ES-DS patients and evaluated their cardiac function class before and after treatment, and the results showed that the effect of targeted drugs on cardiac function class in ES-DS patients was not statistically different [MD = -0.34, 95%CI: (-0.87, 0.19), P = 0.21], but significantly improved cardiac function class in non-DS patients [MD = -0.67, 95%CI: (-0.95, -0.39), P < 0.00001]. Crepaz and Serino found that prolonged bosentan treatment further improved cardiac status, oxygen saturation, and dyspnoea index [18, 19]. Previous studies have shown that newer ERAs such as irisentan and macitentan have less hepatic damage than bosentan, and that irisentan combined with sildenafil may be slightly better than bosentan for cardiac function and cardiac remodeling in patients with congenital heart disease combined with moderate-to-severe PAH [20, 21]. However, the present study did not find that short-term treatment with irisentan and macitentan was effective in improving the 6-follow-up measurements in ES patients. Therefore, the clinical efficacy and safety of these drugs in ES patients need to be further evaluated in large clinical samples.

Selexipag, a selective prostacyclin receptor (IP) agonist, has shown significant benefits in treating PAH by reducing the risk of disease progression and hospitalization [8]. While selexipag has demonstrated efficacy in PAH, its use in ES patients has not been extensively studied. The limited data available suggest that selexipag may be a promising option for ES patients, but further research is needed to establish its efficacy and safety in this specific population. Therefore, we did not include selexipag in our meta-analysis due to the lack of sufficient data on its use in ES patients. Future studies should aim to evaluate the potential benefits of selexipag in ES patients, particularly in those with severe disease or intolerance to other targeted therapies.

This study provides strong evidence supporting the use of targeted therapies to improve exercise tolerance and cardiac function in patients with Eisenmenger syndrome (ES), particularly when administered over the long term. Our comprehensive meta-analysis of 13 studies involving 393 ES patients demonstrates that all three major classes of targeted drugs—endothelin receptor antagonists (ERAs), phosphodiesterase-5 inhibitors (PDE5i), and prostacyclin analogues—significantly enhance 6-minute walk distance (6MWD) and cardiac function. Among these, prostacyclin analogues appear to have the most pronounced effect on improving exercise tolerance and cardiac function.

However, several limitations must be addressed to refine therapeutic strategies and enhance patient outcomes. The sample sizes in some studies, especially those involving patients with Down syndrome (DS), were relatively small, which may limit the generalizability of the findings. Additionally, the lack of placebo-controlled comparisons in the included studies precludes a definitive assessment of the absolute efficacy of these targeted therapies. Future research should focus on larger, placebo-controlled trials to validate these findings and explore the differential efficacy of targeted therapies based on the type of congenital heart disease (e.g., ASD vs. VSD vs. PDA).