Data from: On-demand sildenafil as a treatment for Raynaud phenomenon: a series of n-of-1 trials

Background: Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5
inhibitors has shown moderate efficacy. Adverse effects decrease the
risk–benefit profile of these drugs, and patients may not be willing to
receive long-term treatment. On-demand single doses before or during
exposure to cold may be a good alternative. Objective: To assess the
efficacy and safety of on-demand sildenafil in RP. Design: Series of
randomized, double-blind, n-of-1 trials. (ClinicalTrials.gov:
NCT02050360). Setting: Outpatients at a French university hospital.
Participants: Patients with primary or secondary RP. Intervention: Each
trial consisted of a multiple crossover study in a single patient. Repeat
blocks of 3 periods of on-demand treatment were evaluated: 1 week of
placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil
at 80 mg per dose, with a maximum of 2 doses daily. Measurements: Raynaud
Condition Score (RCS) and frequency and daily duration of attacks. Skin
blood flow in response to cooling also was assessed with laser speckle
contrast imaging. Mixed-effects models were used and parameters were
estimated in a Bayesian framework to determine individual and aggregated
efficacy. Results: 38 patients completed 2 to 5 treatment blocks. On the
basis of aggregated data, the probability that sildenafil at 40 mg or 80
mg was more effective than placebo was greater than 90% for all outcomes
(except for RCS with sildenafil, 80 mg). However, the aggregated effect
size was not clinically relevant. Yet, substantial heterogeneity in
sildenafil's efficacy was observed among participants, with
clinically relevant efficacy in some patients. Limitation: The response to
sildenafil was substantially heterogeneous among patients. Conclusion:
Despite a high probability that sildenafil is superior to placebo,
substantial heterogeneity was observed in patient response and aggregated
results did not show that on-demand sildenafil has clinically relevant
efficacy. In this context, the use of n-of-1 trials may be an original and
relevant approach in RP.