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On-demand sildenafil not superior to placebo for Raynaud's syndrome
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Despite a high probability that on-demand sildenafil is superior to placebo in the treatment of Raynaud’s syndrome, aggregate observed findings failed to demonstrate clinically relevant efficacy, according to data published in the Annals of Internal Medicine.
“I think the most interesting aspects of this work actually come from the discrepancy between the global and individual effects, which was due to important heterogeneity,” Matthieu Roustit, PharmD, PhD, of Grenoble Alpes University Hospital, France, told Healio Rheumatology. “We initially designed a series of n-of-1 trials to deal with such heterogeneity and increase power. We thought this design was particularly relevant in Raynaud, considering between-subject variability, and the on-demand treatment that we proposed.”
To evaluate the safety and efficacy of on-demand sildenafil in patients with Raynaud’s syndrome, Roustit and colleagues conducted a series of double-blind n-of-1 trials, each one consisting of a prospective, multiple-crossover study of a single person. Following a 2-week run-in period, the patients — recruited from a French university hospital — participated in two to five study blocks over the course of two consecutive winters. Each block was broken into three periods of on-demand treatment, including 1 week of placebo, 1 week of sildenafil 40 mg and 1 week of sildenafil 80 mg, with a maximum of two daily doses.
A total of 38 participants with primary or secondary Raynaud’s syndrome completed two to five treatment blocks. The researchers collected measurements including the Raynaud Condition Score (RCS), the frequency and daily duration of attacks and skin blood flow in response to cooling. In addition, they determined individual and aggregated efficacy using mixed-effects models and parameters estimated in a Bayesian framework.
According to the researchers’ aggregated data, the probability that either dosage of sildenafil would be superior to placebo was greater than 90% for all outcomes except for RCS with the 80-mg regimen. However, the aggregated effect size failed to reach clinical relevancy, and the researchers observed substantial heterogeneity in the treatment’s efficacy. Some patients nonetheless demonstrated clinically relevant efficacy with sildenafil.
“On average, the probability of superiority is high, although there was a clinically relevant effect size in only a few patients — but still a few,” Roustit said in an interview. “Heterogeneity is important and individual response is difficult to predict from aggregated results. Very importantly, there was no major safety issue.”
He added, “Our conclusion is that in this particular situation, it may therefore be an ethical and reasonable option to expose all patients. Most treatments tested in Raynaud have shown moderate — if any — efficacy, and this is principally due to important heterogeneity. The n-of-1 approach seems particularly relevant in this situation to see whether a given patient will benefit from the treatment. On-demand sildenafil could be an option in patients who are not willing to take daily medication.” – by Jason Laday
Disclosure: Roustit reports grants from Pfizer France, GIRCI Auvergne Rhône-Alpes and the Association des Sclérodermiques de France during the conduct of the study, as well as grants from Bioprojet and United Therapeutics outside the submitted article. Please see the full study for all other authors’ relevant financial disclosures.
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