Systemic sclerosis (SSc) is an autoimmune disease associated with significant mortality and morbidity. Cardiovascular causes are the single largest contributor to premature death. To date, much of the focus on managing the care of SSc patients has concentrated on traditional risk factors related to fibrotic and microvascular dysfunction. There is, however, evidence of a strong cardiovascular component to the disease and points to macrovascular dysfunction as being a key contributor to the premature mortality associated with SSc. This thesis reports on the conduct of a multi-centre, randomised, placebo-controlled clinical trial (the SSTEP Study). The aim of the study was to assess whether oral Iloprost was more effective than placebo in reducing cardiovascular events and disease progression in SSc.
Two hundred and sixteen patients with systemic sclerosis were recruited, between February 2002 and February 2005, at nine centres in the UK and Ireland. After one month placebo run-in, participants were randomised to either oral Iloprost (50-200mcg daily) or matched placebo. Baseline demographics, disease characteristics and organ screening data were collected, and participants were reviewed annually for endpoint measurements; CV events, SSc disease progression and mortality, with regular safety reviews between these annual visits. Participants were followed up for a period of 4 to 7 years.
Data analysis of the combination of the two measures (survival free from death or a cardiovascular event) demonstrated a trend towards favouring Iloprost over placebo but the difference was not statistically significant (Logrank test: Chi square=0.75, p=0.39). When time to a confirmed cardiovascular endpoint alone was examined there was a suggestion of a benefit from Iloprost, but the difference was again not statistically significant (Logrank test, Chi square =0.82, p=0.37). There was no statistically significant change in the rate at which organ screening endpoints occurred throughout follow-up, and for each endpoint there was no statistically significant difference between results in patients randomised to Iloprost compared to those randomised to placebo. Withdrawal from the treatment to which the patient was randomised was frequent with 97 (45%) of the total participants discontinuing study medication. ‘On treatment’ analysis, undertaken using the endpoint of death or confirmed cardiovascular endpoint, just failed to show statistical significance at the 5% level (p=0.054).
The results of the SSTEP study showed that there was a trend towards favouring oral Iloprost over placebo in systemic sclerosis, though there was no statistically significant evidence to recommend its use to prevent disease progression. The high rate of withdrawal from both Iloprost and placebo hindered the possibility of demonstrating that Iloprost was effective in this study. It cannot be concluded that it is a useful therapy that may prevent premature mortality or progression to cardiovascular disease in this patient group.
|Date of Award||2014|
|Sponsors||Raynaud's and Schleroderma Association|
|Supervisor||Jill Belch (Supervisor) & Faisel Khan (Supervisor)|
- Systemic sclerosis
- Cardiovascular disease