In this long-term analysis, treatment of adult ES patients with Down’s syndrome with bosentan for a mean period of more than 4 years resulted in significant initial improvements in SaO2 at rest and 6MWD that were sustained during follow-up. Treatment options for patients with ES are limited, with the BREATHE-5 study being the only placebo-controlled study in this population . It demonstrated that bosentan significantly reduced pulmonary vascular resistance index and mean pulmonary arterial pressure and significantly improved 6MWD in ES patients in WHO functional class III. Safety (change from baseline in SpO2) was the primary endpoint in the BREATHE-5 study and the authors demonstrated that bosentan did not worsen oxygen saturation. Data from a number of studies, including the current study, have since confirmed these benefits in the longer term in patients with PAH-CHD and specifically in patients with ES [19, 21, 25–28]. In addition, PAH-specific therapy has been shown to significantly lower the all-cause mortality rate in a large population of ES patients, providing strong conceptual support for treatment of all ES patients with PAH-specific therapy .
Patients with Down’s syndrome are at risk of developing PAH earlier than patients without Down’s syndrome and have worse functional capacity . Both these factors are associated with poor long-term outcome [4, 5, 29–31]. There are no randomized controlled trials in this subpopulation of PAH-CHD patients. The results of our long-term analysis support data from previous open-label studies, which have demonstrated the efficacy of bosentan in ES patients with Down’s syndrome [19–21], and suggest that up to 4 years’ treatment can be beneficial in these patients. A previous study has shown that there was no significant difference in mortality between ES patients with and without Down’s syndrome after 4 years of bosentan treatment . Similarly, no differences in the efficacy of bosentan between PAH-CHD patients with and without Down’s syndrome in a 12-month study have been reported, with both groups showing significant improvements in 6MWD, WHO functional class and haemodynamics .
The validity of the 6MWT in patients with Down’s syndrome has been questioned as it has been reported that level of intellectual disability is an independent factor for 6MWD . Vis and coworkers showed that there was a significant difference in mean 6MWD between the group with a mild/moderate level of intellectual disability (318 ± 92 metres) and the group with a severe/profound level of intellectual disability (195 ± 84 metres). In our study, patients had a low level of intellectual disability; however, 6MWD was in the range seen in patients with severe intellectual disability in the Vis study. Importantly in the current study, patients achieved a significant increase in 6MWD with long-term bosentan therapy. These findings are similar to those from a recently published series of patients which demonstrated that 6MWD increased in patients with Down’s syndrome during the first 12 months of bosentan therapy – achieving early significance – and this improvement from baseline was maintained during a further 24 months of therapy . Although it has been shown that there is no discrepancy between improvement in 6MWD and haemodynamic parameters in patients with Down’s syndrome , it is clear from the contrasting results from published small studies that we still need to understand more about use of the 6MWT in this population. Consequently, although there is some debate about the most appropriate assessment in this patient population, evidence of bosentan efficacy has been demonstrated. Based on our experience, we believe that patients’ compliance – in the presence of mild intellectual disability – is sufficient to guarantee a reliable result as confirmed by the assessment of objective parameters.
In the present study we did not perform an invasive evaluation such as right heart catheterization during follow-up visits. However, several studies report a high correlation (0.57 to 0.93) between echocardiographic and haemodynamic measurements of pulmonary arterial systolic pressure and, therefore, the echocardiographic assessment used in the current analysis provides valid information [33–35]. Baseline values of TR velocity and pulmonary arterial systolic pressure in the patients included in the current study were higher than those associated with the presence of pulmonary hypertension as specified in the current guidelines . Additional variables to confirm the presence of pulmonary hypertension were also included in accordance with the guidelines (i.e. increased pulmonary valve regurgitation velocity, shortened acceleration time of RV ejection into the pulmonary artery, increased dimensions of the right heart chambers, abnormal shape and function of the interventricular septum and increased right ventricular wall thickness and pericardial effusion were demonstrated).
WHO functional class remained stable in the majority of patients during treatment, with an improvement in functional class being achieved by one patient. In the BREATHE-5 study, pulmonary vascular resistance index increased in the placebo arm during the 16-week study period, demonstrating the progressive nature of ES . As a result, the maintenance of patients in WHO functional class III during prolonged bosentan therapy is encouraging.
The long-term results from this study provide confirmation of the significant improvement in exercise capacity and SpO2 in ES patients with Down’s syndrome seen in previous studies [17, 20, 21]. Additionally, this improvement was quick and progressive (in the first 6 months) and was then stable for up to 48 months.
Our study has some limitations, specifically the small number of patients and the lack of a placebo-controlled group and that data are only confirmed by echocardiography and not by right heart catheterization. However, it represents, with few other studies, one of the largest series of ES patients with Down’s syndrome treated with bosentan for an extended period. As a result the significant and stable increase in 6MWD and oxygen saturation are of clinical relevance.