Advice
Key points from the evidence
Key points from the evidence
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The content of this evidence summary was up-to-date in March 2015. See summaries of product characteristics (SPCs), British national formulary (BNF) or the MHRA or NICE websites for up-to-date information. |
Summary
Data on the efficacy of sildenafil for managing digital ulcers associated with systemic sclerosis are limited. Individual randomised controlled trials (RCTs) have not shown a statistically significant treatment effect of sildenafil on digital ulcers. However, a small observational study has shown some benefit for sildenafil on ulcer healing and a meta‑analysis has shown benefit for phosphodiesterase type 5 (PDE5) inhibitors as a drug class for ulcer healing and improvement. Larger RCTs, particularly with other comparative treatments, are needed to clarify efficacy and safety of using sildenafil for managing digital ulcers.
Regulatory status: off-label. This topic was prioritised because there was a high volume of requests from the NHS. PDE5 inhibitors, such as sildenafil, are used in the management of digital ulcers, but none is specifically licensed for this indication. NHS England has published a draft clinical commissioning policy on sildenafil and bosentan for the treatment of digital ulceration in systemic sclerosis which is currently undergoing a 3‑month public consultation (consultation ends 30 April 2015).
The Department of Health has amended regulations to allow unrestricted prescribing of generic sildenafil for men with erectile dysfunction.
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Effectiveness
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Safety
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Patient factors
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Resource implications
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Introduction and current guidance
Digital ulcers usually occur in people who have severe Raynaud's phenomenon secondary to systemic sclerosis (Steen et al. 2009), and are associated with fibrosis and diseased blood vessels in fingers or toes (digital vasculopathy).
Digital ulcers are difficult to treat, painful, may limit hand function, can develop into serious complications and impair overall quality of life. Treatment aims to improve symptoms, prevent and heal ulcers, and reduce associated morbidity and mortality.
The European League against Rheumatism (EULAR) Scleroderma Trials and Research group published recommendations for managing systemic sclerosis‑related digital vasculopathy in 2009 (Kowal-Bielecka et al. 2009). No formal recommendation on using sildenafil was included. However, consensus best practice recommendations for digital vasculopathy developed by the UK Scleroderma Study Group advocate using PDE5 inhibitors, such as sildenafil and tadalafil, as a treatment option for ulcers that are difficult to treat. An update of the EULAR recommendations is expected in 2015.
Full text of introduction and current guidance.
Product overview
Sildenafil is a PDE5 inhibitor with a vasodilator effect. Sildenafil is licensed in the UK for treating pulmonary hypertension in adults and children, and for treating erectile dysfunction in men. Prescribing of generic sildenafil is unrestricted for men with erectile dysfunction.
See the summaries of product characteristics of sildenafil products for more information on these indications. No sildenafil product is licensed for managing digital ulcers; therefore using sildenafil for this indication is off‑label.
Full text of product overview.
Evidence review
Systemic sclerosis is a rare condition and RCTs in this area are difficult to undertake. Data on managing digital ulcers with sildenafil are therefore very limited. This evidence summary is based on the best available evidence for using sildenafil to manage digital ulcers in people with systemic sclerosis, including 2 small RCTs (Fries et al. 2005 and Herrick et al. 2011) and 1 observational study (Brueckner et al. 2010). In the original published papers of the 2 RCTs, data on ulcer healing were not reported. However, outcome data were collated and evaluated in a meta-analysis that focused on healing and preventing digital ulcers (Tingey et al. 2013). The meta‑analysis considered PDE5 inhibitors as a drug class, and the pooled analysis included results from the 2 RCTs of sildenafil (Fries et al. 2005 and Herrick et al. 2011) and an RCT of tadalafil (Shenoy et al. 2010).
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Both RCTs considered the effect of sildenafil in people with Raynaud's phenomenon generally secondary to systemic sclerosis. The smaller, single‑centre, German crossover study (n=20) compared sildenafil (50 mg twice daily) with placebo for 4 weeks (Fries et al. 2005) and the second larger, multicentre European RCT (n=57; Herrick et al. 2011) compared modified‑release sildenafil (titrated up to 200 mg daily, equivalent to 150 mg immediate release) with placebo for 28 days. The effect of sildenafil on ulcers was a primary outcome in the crossover study but only an exploratory outcome in the second, larger RCT.
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In Fries et al. (2005), all 6 people with ulcers at baseline reported some healing during treatment with sildenafil, and ulcers completely healed in 2 people (no statistical data analysis reported).
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In Herrick et.al. (2011), the per‑protocol population was 45 people (sildenafil, n=20; placebo, n=25). Five (25%) people had digital ulcers at baseline compared with 3 (15%) people after 28 days of treatment with sildenafil. In the placebo group, 3 (12%) people had digital ulcers at baseline compared with 5 (20%) people at day 28. No data analysis was reported for ulcer healing and data on the number of people with ulcers were only included in an abstract (Herrick et al. 2009).
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The meta-analysis (Tingey et al. 2013) reported that there was no statistically significant benefit of sildenafil compared with placebo for ulcer healing (p=0.27 and p=0.39) or ulcer improvement (p=0.06) in the individual trials. However, these trials were underpowered for these end points. The meta‑analysis pooled effect for PDE5 inhibitors as a class (including trials of sildenafil and tadalafil) showed a statistically significant benefit compared with placebo for digital ulcer healing (RR 3.28, 95% confidence interval [CI] 1.32 to 8.13, p=0.01) and digital ulcer improvement (RR 4.29, 95% CI 1.73 to 10.66, p=0.002).
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Observational data from a small, single‑centre pilot study (n=19; Brueckner et al. 2010), which considered maximally tolerated doses of sildenafil (up to 150 mg daily, mean daily dose 114 mg) for a mean duration of 5.2 months, found a statistically significant reduction in the number of digital ulcers from baseline (mean difference 2 ulcers per person, p<0.001). However, 9 people developed 12 new ulcers between them.
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Across both RCTs (Fries et al. 2005 and Herrick et al. 2011) more people experienced adverse events in the sildenafil groups compared with the placebo groups. The most common adverse event for people taking sildenafil was headache (20% in Fries et al. 2005 and 50% in Herrick et al. 2011). Other less frequent adverse events included dyspepsia, arthralgia and myalgia. No deaths or serious adverse events were reported. A total of 6 people across both studies stopped taking sildenafil because of treatment‑related adverse effects (mainly headache and myalgia).
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In the observational study (Brueckner et al. 2010), mild adverse effects were common (47%). Adverse effects included palpitations (21%), facial flushing (21%) and peripheral oedema (16%). In 3 people with hypertension, antihypertensive treatment was reduced during sildenafil treatment. Two people stopped treatment because of adverse effects.
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The small RCTs and the observational study have a number of limitations and the results are difficult to relate to clinical practice. In particular, the literature highlights the difficulty investigators faced defining and standardising digital ulcer indicators and end points when undertaking research in this area.
Full text of evidence review.
Context and estimated impact for the NHS
The estimated 28‑day cost of generic sildenafil at a dose of 25 mg to 50 mg 3 times daily is £22.89 to £23.73 (Drug Tariff February 2015; excluding VAT). The oral sildenafil product licensed for pulmonary hypertension (Revatio) is more expensive, at an estimated 28‑day cost of £416.58 for 20 mg 3 times daily (MIMS February 2015; excluding VAT). Consensus best practice recommendations for digital vasculopathy include the use of bosentan and prostanoids such as iloprost in some people. Bosentan, taken orally, is licensed for preventing digital ulcers in people with systemic sclerosis and pre‑existing ulcers (it has not been shown to heal existing digital ulcers). Iloprost injection is unlicensed in the UK but can be supplied on request from the manufacturer. Iloprost is given by infusion, which involves admission to hospital as either a day case or as an inpatient.
Full text of context and estimated impact for the NHS.
Information for the public
A plain English summary is available on the NICE website. This sets out the main points from the evidence summary in non‑technical language and may be especially helpful for people with digital ulcers who are thinking about trying sildenafil.
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About this evidence summary 'Evidence summaries: unlicensed or off‑label medicines' summarise the published evidence for selected unlicensed or off‑label medicines that are considered to be of significance to the NHS, where there are no clinically appropriate licensed alternatives. The summaries provide information for clinicians and patients to inform their decision‑making and support the construction and updating of local formularies. The summaries support decision‑making on the use of an unlicensed or off‑label medicine for an individual patient, where there are good clinical reasons for its use, usually when there is no licensed medicine for the condition requiring treatment, or the licensed medicine is not appropriate for that individual. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary, but this summary is not NICE guidance. |