On-Demand Sildenafil as a Treatment for Raynaud Phenomenon

Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease

“…RP is a condition characterised by episodic cold-or stress-induced ischaemic vasospastic episodes affecting the digital arteries and arterioles leading to ulcerations and necrosis and is either idiopathic (primary RP) or due to connective tissue disease (secondary RP). A recent meta-analysis of six RCTs that included 244 patients with secondary RP, predominantly due to scleroderma, found that PDE5I therapy moderately reduced the daily frequency and duration of vasospastic attacks and promoted visible healing of ulcers (Roustit, Blaise et al, 2013) and a prospective crossover study suggests that these beneficial effects also extend to primary RP (Caglayan, Huntgeburth et al, 2006). These findings suggest that PDE5I therapy may have an equivalent effect on vasospastic attack frequency to first-line treatment with calcium channel blockers (CCBs) and is more successful at reducing attack frequency and promoting ulcer healing than ERAs, an effective and approved treatment for reducing digital ulceration in scleroderma but which has inconsistent or minimal effects on other clinical parameters and is of uncertain benefit in primary RP (Roustit, Blaise et al, 2013).…”

“…A recent meta-analysis of six RCTs that included 244 patients with secondary RP, predominantly due to scleroderma, found that PDE5I therapy moderately reduced the daily frequency and duration of vasospastic attacks and promoted visible healing of ulcers (Roustit, Blaise et al, 2013) and a prospective crossover study suggests that these beneficial effects also extend to primary RP (Caglayan, Huntgeburth et al, 2006). These findings suggest that PDE5I therapy may have an equivalent effect on vasospastic attack frequency to first-line treatment with calcium channel blockers (CCBs) and is more successful at reducing attack frequency and promoting ulcer healing than ERAs, an effective and approved treatment for reducing digital ulceration in scleroderma but which has inconsistent or minimal effects on other clinical parameters and is of uncertain benefit in primary RP (Roustit, Blaise et al, 2013). Moreover, recent interventional trials (Table 3) have demonstrated a significant improvement in digital blood flow in patients with secondary RP following the use of both oral and topical sildenafil preparations (Andrigueti, Ebbing et al, 2017;Wortsman, Del Barrio-Díaz et al, 2018), and a recent RCT showed that chronic treatment with sildenafil improved healing of digital ulcers secondary to systemic sclerosis (Hachulla, Hatron et al, 2016).…”

“…Although there has been little research into the therapeutic efficacy of PDE5Is in primary RP, subgroup analysis of a recent RCT investigating chronic vardenafil use in 53 adults with mixed RP revealed an increased efficacy in patients with primary RP (Caglayan, Axmann et al, 2012). However, significant clinical improvement was not replicated in a series of n ‐of‐1 trials of increasing sildenafil dosage in 38 patients with mixed RP (68% of whom had primary RP), which demonstrated a markedly heterogenous response (Roustit, Giai et al, 2018). Therefore, although PDE5I therapy may represent a promising intervention for improving the microcirculation and clinical outcomes of patients with RP, further research with clearer stratification of RP causality, direct comparison with oral CCBs, and standardised tools for assessment of digital blood flow is necessary to clarify the efficacy and safety of these agents and determine which group of patients may benefit most from treatment.…”

Management of Raynaud’s phenomenon in systemic sclerosis—a practical approach

“…Recently, a randomized, double-blind, N-of-one trial in primary and secondary RP patients compared on-demand treatment (before exposure to triggers or at the beginning of an attack) using placebo versus sildenafil in two different doses (40 and 80 mg). 19 The study showed that on-demand sildenafil was not superior; with high heterogeneity and a small effect size, but stated that the likelihood of sildenafil being more effective than placebo was 90%. A double-blinded RCT comparing udenafil versus amlodipine showed no differences in the treatment of secondary RP.…”

Personal preferences for Personalised Trials among patients with chronic diseases: an empirical Bayesian analysis of a conjoint survey

“…As a result, some have placed Personalised Trials at the top of the methodological hierarchy of evidence-based medicine for informing treatment decisions. 4 Recently, there has been renewed interest in using Personalised Trials for a variety of conditions, [9][10][11][12] however, their clinical practice remains scattered due, in part, to insufficient patient acceptability and demand. [13][14][15] With a goal of increasing the adoption of Personalised Trials into clinical practice, we developed a 'collaboratory' comprising a diverse pool of stakeholders-including patients-relevant to the design and implementation of Personalised Trials.…”