85 Patients receiving sitaxsentan at 100 mg had 96% overall survival and a 34% risk for a clinical worsening and a 15% risk of discontinuation due to adverse events after a year of treatment. Bosentan in comparison had an 88% overall survival, DNA-PK activation a 40% risk of a clinical worsening and 30% risk of discontinuation due to adverse events. The risk of elevated aminotransferase and/or alanine aminotransferase was 6% of the sitaxsentan group and 14% for the bosentan group. It has been suggested that based on the two STRIDE-2 trials
the use of a highly selective ETA-receptor antagonist such as sitaxsentan is advantageous compared to a non-selective ETA/B receptor antagonist such as bosentan. 86 There have been a number of other STRIDE trials. The STRIDE-6 trial compared the effectiveness of sitaxsentan in a group of patients who had to discontinue treatment with bosentan due to a lack of efficacy or skin or liver problems. 87 The 6-minute walk test improved by 15% in 5 out of 15 patients taking 100 mg of sitaxsentan. This was a small study involving only 48 patients and lacked a placebo group. Other STRIDE trials, or long-term extension to trials include the STRIDE-4, STRIDE-1X, STRIDE-3, STRU and STRIDE-X trials. 88 Despite approval for marketing sitaxsentan in Europe, Canada and Australia in 2006, the FDA refused approval due to concerns about the efficacy of the drug in the STRIDE-2
trial. The STRIDE-5 trial was planned to address these issues, as were a series of trials in the USA, designed to compare the efficacy and safety of sitaxsentan
with sildenafil (Clinicaltrials.gov identifiers: NCT00795639, NCT00796666 and NCT00796510). However, in 2010 the manufacturer, Pfizer, due to 2 cases of idiosyncratic, fatal hepatic failure associated with sitaxsentan use, terminated these trials. 89 As a consequence the drug was voluntarily withdrawn from worldwide use on the 10th December 2010. Macitentan Macitentan (Opsumit) is a mixed ETA/ETB receptor antagonist that was developed by modifying the structure of bosentan to make sulphonamide derivatives. 90 The tert-butyl benzene sulfonamide part of the initial compound was then replaced by a series of simple alkyl sulfamide moieties (Figure 8). This yielded a series of compounds with differing efficacy at the ETA and ETB receptor. One of these compounds, macitentan, emerged AV-951 has having improved tissue penetration and high affinity for both receptors. 91 Doses required to achieve the similar effect of bosentan were an order of magnitude lower for macitentan. The efficacy of the drug is contributed to by the formation of its metabolite ACT-132577, formed by oxidative depropylation, which also has antagonistic activity at ETA and ETB receptors. 91 Macitentan is slowly absorbed and has a half-life of between 6–8.5 and 14–18.5 hours depending on dose.