Sildenafil (Viagra) provided some benefits for digital ulcer healing in patients with systemic sclerosis (SSc), although the primary endpoint of a placebo-controlled trial was not met, French researchers reported.
Compared with patients receiving placebo, the hazard ratio for healing of digital ulcers among patients randomized to sildenafil, 20 mg three times daily for 12 weeks, was 1.33 (95% CI 0.88-2, P=0.18) in an unadjusted analysis and 1.27 (95% CI 0.85-1.89, P=0.25) in an analysis adjusted for the number of ulcers present at baseline, according to Eric Hachulla, MD, PhD, of the Scleroderma National Center, University de Lille, and colleagues.
Nonetheless, the mean number of digital ulcers per patient was significantly lower in the sildenafil group at week 8 (ratio 0.69, 95% CI 0.47-0.99, P=0.04) and week 12 (ratio 0.57, 95% CI 0.37-0.88, P=0.01), the researchers reported online in Annals of the Rheumatic Diseases.
The failure to meet the primary endpoint could have resulted from an unexpectedly high placebo response, they explained.
“In cross-sectional studies involving patients with SSc, the frequency of ischemic digital ulcers was 12% to 16%, with a major impact on hand function and quality of life,” they wrote.
But minimal success has been seen thus far with treatment. One drug that has been evaluated is bosentan (Tracleer), which was beneficial in decreasing the occurrence of new ulcers but lacked efficacy in increasing the time to healing.
Sildenafil is a phosphodiesterase type 5 (PDE-5) inhibitor that blocks cyclic guanosine monophosphate breakdown, which lowers intracellular calcium and leads to smooth muscle relaxation.
“Because of their vasodilating, angiogenic, and decreased platelet aggregation properties, PDE-5 inhibitors may have a potentially beneficial effect on digital ulcer healing,” stated Hachulla and colleagues.
And small studies of both sildenafil and tadalafil (Cialis) suggested a potential benefit, so the investigators undertook a prospective study in 25 centers that included 83 patients with 192 digital ulcers at entry.
Patients’ mean age was 49, and more than three-quarters were women. Mean time since the onset of symptoms other than Raynaud’s phenomenon was just under 7 years.
The mean number of ulcers per patient was 2.5 in the placebo group and 2.1 in the sildenafil group, and almost all patients had at least one digital ulcer 2 mm in diameter or greater.
Pain intensity was reported as being 59 on a 100-mm scale the previous week, the Health Assessment Questionnaire disability index was 1, and hand disability was scored as 30 out of a possible 90 on the Cochin hand function scale.
Secondary outcomes also favored sildenafil, although statistical significance again was not met. For example, in 70.3% of patients in the sildenafil group, all baseline ulcers had healed by week 12, compared with 60.5% of the placebo group (OR 1.50, 95% CI 0.52-4.37, P=0.45).
In addition, 67.6% of sildenafil patients and 48.7% of placebo patients were free of ulcers at week 12 (OR 2.20, 95% CI 0.86-5.65, P=0.10).
Moreover, new digital ulcers appeared between weeks 4 and 12 in 21.6% of patients receiving sildenafil but in 39.5% of those given placebo (OR 0.42, 95% CI 0.15-1.17, P=0.10).
Significant differences between the active treatment and placebo also were not found in the subgroup of patients who were receiving concomitant bosentan after adjustment for disease severity.
Four patients experienced complications of the digital ulcers. One patient in the sildenafil group developed a skin infection and gangrene, while three placebo patients had skin infections. Five patients in the sildenafil group discontinued treatment for adverse events such as syncope and rash, as did three in the placebo group because of events such as leg edema and headache.
In discussing possible reasons for the limited efficacy seen in the study, Hachulla and colleagues noted that 66% of ulcers that were present at the time of study entry had healed by week 12 in the placebo group, which was more than twice what they had expected based on an earlier study.
“Since all participating centers were highly experienced in the treatment of SSc and digital ulcers, the local digital ulcer treatment provided was certainly more effective than the treatment given 10 years ago,” they stated.
Furthermore, more than half of the placebo patients were on vasodilating calcium channel blockers, which were found in a retrospective study to decrease the risk of these ulcers in SSc.
A limitation of the study was the possibility that too low a dosage of sildenafil was used. In pulmonary arterial hypertension, the drug has been given in dosages as high as 80 mg three times per day.