1. Macitentan, an endothelin-1 blocker, did not reduce the number of new digital ulcers in patients with systemic sclerosis.
2. Macitentan was generally well-tolerated, but was linked with increased incidence of headache, peripheral edema, skin ulcer, anemia, respiratory tract infection, diarrhea, and nasopharyngitis.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Systemic sclerosis is a chronic autoimmune disease that manifests with digital ischemia, arterial hypertension, and renal crisis, among others. Digital ulcers, secondary to digital ischemia, are common in this disease, and are associated with pain, disability, and poor quality of life. Endothelin-1 is a mediator of vascular hypertrophy, inflammation, and fibrosis, and its role has been hypothesized in the development of digital ulcers. This clinical trial tested an endothelin-1 blocker, macitentan, in patients with systemic sclerosis, and found that it was no more effective than placebo in reducing the rate of new digital ulcers. Generally, macitentan was well tolerated, but had side effects including headache, peripheral edema, skin ulcers, anemia, respiratory tract infection, diarrhea, and nasopharyngitis.
While macitentan represents a potential new therapy for digital ulcers in this patient population, this study was limited in a number of ways. For one, there was no clear classification system for digital ulcers. Given the multiple study sites, this factor negatively impacted inter-rater reliability from center to center. Other limitations included a wide variation in physician practices and standard guidelines between study sites, and a lower-than-expected incidence of new digital ulcers after 16-weeks, potentially reducing the power of the study to detect the effect of macitentan. Overall, the study suggests that macitentan does not significantly reduce digital ulcers in patients with systemic sclerosis, and therefore its use is not supported for this patient population.
In-Depth [randomized control trial]: This study aimed to quantify the effects of macitentan, an endothelin-1 blocker, in preventing new digital ulcers in patients with systemic sclerosis. It was run in 2 parallel trials with identical primary outcome measures; the average number of new digital ulcers from baseline to 16 weeks of follow-up. In the first trial, a total of 285 patients were enrolled and randomized into 3 cohorts, receiving 3 mg macitentan, 10 mg macitentan, or placebo. Comparing the 3 mg dose of macitentan to placebo, there was an absolute difference of new digital ulcers of 0.09 (95%CI, -0.37 to 0.54), with a rate ratio of 1.10 (95%CI, 0.66 to 1.83, p = 0.71). With the higher dose of 10 mg of macitentan the absolute difference was 0.23 (95%CI, -0.27 to 0.72) and the rate ratio was 1.27 (95%CI, 0.76 to 2.11, p = 0.36).
The second trial was run coincidentally with the first and it enrolled 265 patients and randomized them to receive the same 2 doses of macitentan or placebo. This trial was halted early after an independent data monitoring committee found that macitentan had little effect. By the time of cessation, 74% of patients had completed the 16 weeks of treatment. Among these participants, the absolute difference in new digital ulcers was 0.23 (95%CI, -0.35 to 0.82) and 0.25 (95%CI, -0.34 to 0.84) for the 3 mg and 10 mg doses of macitentan respectively.
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