The drug sildenafil reduced the frequency of attacks of Raynaud's phenomenon secondary to limited cutaneous systemic sclerosis in a small, randomized, placebo-controlled trial that was reported in Arthritis & Rheumatism.
The study enrolled 57 men and women aged 18-75 years, all of whom both had a diagnosis of Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis and experienced at least 7 attacks per week. Patients were randomized to receive modified-release sildenafil (100 mg once daily for 3 days, titrated to 200 mg once daily for 25 days) or placebo, reported Dr. Ariane Herrick of the University of Manchester (England) and her associates (Arthritis Rheum. 2011;63:775-82).
Of the 57 people originally enrolled, 20 in the treatment group and 25 controls completed the 28-day study and were entered into analysis. Patients kept treatment diaries before and during the study period, recording the duration and pain intensity of each attack; serum samples were taken on days 1, 7, and 28.
The primary end point was the percent change in the number of weekly RP attacks. Secondary end points measured the severity and duration of attacks.
After 28 days, the mean number of RP attacks per week lessened from 25 at baseline to 19 in the control arm, and from 31 at baseline to 19 in the treatment arm, with a mean percent reduction of 44% in the treatment arm, compared with 18% in the control arm (P = .034). Statistically insignificant differences were noted between the groups for Raynaud’s Condition Score, duration of attacks, pain score, endothelial dysfunction, or serum biomarkers associated with RP. The most frequent adverse events reported were headache and dyspepsia.
Dr. Ulf Müller-Ladner, professor of internal medicine and rheumatology at Justus-Liebig University Giessen (Germany), said in an interview that this "is a very important study, as we do not have too many controlled clinical trials for Raynaud’s, and every controlled study showing efficacy is very helpful for daily practice." The investigators acknowledged the study’s small size and high attrition from the intention-to-treat sildenafil arm as limitations, particularly as the study was no longer powered to detect secondary end points. Also disappointing, they wrote, was that the endothelial dysfunction measures and the serum levels of biomarkers were similar between the groups.
The study's short duration was another possible limitation. The findings from an earlier, longer (5.2-month) study of sildenafil in 16 patients with systemic sclerosis – of whom 7 had limited cutaneous involvement – showed statistically significant lessening of attack pain associated with RP with the maximum tolerated dose of sildenafil (Ann. Rheum. Dis. 2010;69:1475-8).
Finally, they noted, the modified-release formulation of sildenafil may not have provided the most effective dose for the patient population studied.
Dr. Müller-Ladner agreed with the description of the study's design weaknesses: "The shortcomings of the present study are its placebo arm and its short duration. These results must be confirmed through the initiation of a large, multinational, longer-term trial."
The trial was funded by Pfizer, the drug's manufacturer. Dr. Herrick acknowledged financial relationships with Actelion, Mediquest, Pfizer, and United Therapeutics. Several of the coinvestigators also made relevant financial disclosures. Dr. Müller-Ladner had no relevant financial disclosures.