Fifteen double-blind RCTs were included (n=1,664). Twelve of these studies were reported in peer-reviewed journals. The review also included seven abstract only papers (n=1144) and some open-label extension reports, but these are not included in this abstract since few details were reported.
The results reported below focus on primary outcomes in the 12 included fully-published RCTs and adverse events. Other results and results from open-label extensions and abstracts were also reported in the review.
Bosentan versus placebo (5 RCTs, n=453).
Three RCTs reported statistically significant increases in 6MWD in patients allocated to bosentan compared with placebo: differences of 76 metres (p=0.021), 44 metres (p<0.001) and 53 metres (p=0.008). An additional RCT compared the combination of bosentan plus iloprost with placebo and found a non-statistically significant increase in 6MWD (26 metres; p=0.051), and a statistically significant improvement in New York Heart Association status (34% improved by one class versus 6%, p=0.002) and a significant delay in the time to clinical worsening (p=0.0219). Two studies reported no significant difference in adverse events between treatment groups; the largest study reported an increase in abnormal hepatic function in the bosentan group but similar numbers of other adverse events between treatment groups. The combination treatment was well tolerated: overall, 2 patients withdrew due to adverse events.
One RCT (n=33) reported no significant difference in total pulmonary resistance between bosentan plus epoprostenol and epoprostenol alone, but more patients withdrew in the bosentan-epoprostenol group (4 withdrawals versus 1).
Sildenafil versus placebo (3 RCTs, n=320).
One crossover RCT (n=22) reported that sildenafil was associated with a statistically significant increase in exercise time on the treadmill compared with placebo (44% increase; p<0.0001). Minor adverse effects were associated with placebo, but no patients discontinued treatment due to adverse events. One RCT (n=278) reported a statistically significant increase in 6MWD in patients allocated to sildenafil compared with placebo (p<0.001). Serious adverse events considered to be related to sildenafil were reported in 2 patients. Epistaxis was more common among patients taking sildenafil plus warfarin. One crossover RCT (n=20) that compared sildenafil with placebo reported a statistically significant increase in 6MWD from baseline (p<0.0001). No serious adverse events were reported.
Sitaxsenten (2 fully published RCTs).
One RCT (n=178) reported a statistically significant increase in peak VO2 in patients allocated to 300 mg sitaxsenten compared with placebo (p<0.01), but no difference between 100 mg sitaxsenten and placebo. No ‘clinically meaningful’ differences in adverse events were reported between treatment groups. One RCT (n=185) reported a statistically significant increase in 6MWD in patients allocated to 100 mg sitaxsenten compared with placebo (difference 31.4 metres; p=0.03), but no significant difference between 50 mg sitaxsenten and placebo. No differences in the number of patients with adverse events were reported between treatment groups.
Ambrisentan (1 RCT).
This study (n=64) reported a statistically significant increase in 6MWD in patients allocated to ambrisentan (1 to 10 mg/day) compared with placebo (36 metres; p<0.001). The RCT reported no ‘clinically meaningful’ differences in adverse events between treatment groups.