Sildenafil for Erectile Dysfunction: Trials and AUA Guideline

Does sildenafil have a GRADE rating?

No. The American Urological Association's 2018 erectile dysfunction guideline used its own system instead of GRADE: each evidence-based statement received a body-of-evidence grade of A, B or C and a designation of Strong, Moderate or Conditional, and other advice was given as Clinical Principles or Expert Opinions [1]. The guideline abstract does not say what the guideline recommends about PDE5 inhibitors specifically. It states that, using shared decision-making, all patients should be informed of all treatment modalities that are not contraindicated, regardless of invasiveness or irreversibility, as potential first-line treatments [1].

What did the pivotal trial measure?

Goldstein and colleagues published two sequential double-blind studies in 1998 [2]. The first gave 532 men with organic, psychogenic or mixed erectile dysfunction sildenafil 25, 50 or 100 mg, or placebo, for 24 weeks. The second gave 329 different men sildenafil or placebo for 12 weeks, escalating to 100 mg based on efficacy and tolerance [2].

In the dose-response study, higher doses improved scores for achieving and maintaining erections (P<0.001), and men on 100 mg doubled their mean score for achieving an erection, from 2.0 to 4.0 out of 5 [2]. In the last four weeks of the flexible-dose study, 69% of intercourse attempts were successful with sildenafil versus 22% with placebo (P<0.001) [2].

What do pooled data add?

A 2009 meta-analysis of oral PDE5 inhibitors as a class found better intercourse success than placebo (69.0% versus 35.0%) and more men with improved erections (67% to 89% versus 27% to 35%). Any adverse event was more likely with sildenafil than placebo, relative risk 1.72 (95% CI 1.53 to 1.93); the data came mainly from short-term trials, and many trials were of low methodological and reporting quality [6].

A pooled analysis of 11 double-blind, placebo-controlled flexible-dose studies (2,667 men aged 23 to 89) found improved erectile function with sildenafil across all efficacy measures versus placebo (P<0.02 to P<0.0001) [4].

What does the label add?

The Viagra label covers the 25, 50 and 100 mg tablets for erectile dysfunction; the 20 mg strength belongs to Revatio, a different product for pulmonary arterial hypertension [3][7]. Viagra tablets are prescription products [3]. The Viagra label gives 50 mg as needed about 1 hour before sexual activity, usable from 30 minutes to 4 hours beforehand and no more than once a day, with adjustment to 100 mg or 25 mg [5].

In fixed-dose trials at 50 mg, headache occurred in 21% versus 7% with placebo, flushing in 19% versus 2%, dyspepsia in 9% versus 2% and abnormal vision in 2% versus 1% [5].

What are the main safety warnings?

The Viagra label contraindicates nitrates in any form, whether used regularly or intermittently, and riociguat. It gives no safe waiting time for nitrates after sildenafil, because it is unknown when nitrates can safely be given [5]. An erection lasting more than 4 hours needs immediate medical help [5]. Sudden vision loss in one or both eyes can be non-arteritic anterior ischemic optic neuropathy, reported rarely with PDE5 inhibitors, and sudden hearing loss has also been reported; the label advises stopping the drug and seeking medical care for either [5].