Nifedipine Cream Versus Sildenafil Cream for Patients with Secondary Raynaud Phenomenon: A Randomized, Double-Blind, Controlled Pilot Study.

To the Editor: Topical vasodilators may act as an adjuvant therapy for Raynaud phenomenon (RP). Several trials have shown the benefits of topical nitrates,1Tucker A.T. Pearson R.M. Cooke E.D. Benjamin N. Effect of nitric-oxide-generating system on microcirculatory blood flow in skin of patients with severe Raynaud's syndrome: a randomised trial.Lancet. 1999; 354: 1670-1675Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 2Kan C. Akimoto S. Abe M. Okada K. Ishikawa O. Preliminary thermographic evaluation of new nitroglycerine tape on the peripheral circulatory disturbance in systemic sclerosis.Ann Rheum Dis. 2002; 61: 177-179Crossref PubMed Scopus (29) Google Scholar but there is a lack of evidence for the efficacy of other topical agents. The objective of the study was to compare the vasodilator efficacy of topical 10% nifedipine versus 5% sildenafil in subjects with secondary RP associated with connective tissue disease. A prospective study was performed including 10 patients with secondary RP. We excluded tobacco smokers, patients with primary RP, hypotension, hypertension, myocardial infarction, stroke, or arrhythmia. Patients who were being treated with a vasodilator were required to discontinue use for at least 24 hours before randomization. Patients’ hands were randomized to treatment with 5 g of 10% nifedipine cream on one hand and 5 g of 5% sildenafil cream to the opposite hand. Vinyl gloves were supplied to improve topical absorption, leaving the thumbs out of the gloves without any cream (control group). All patients underwent a high-frequency color Doppler ultrasound examination before and 1 hour after topical application. The temperature of the waiting and examination rooms was set at 66°F. The radiologist was blinded to the treatment groups, and subsequent analysis was blinded to ultrasound results. The primary outcome was the improvement of blood flow in digital arteries using the peak systolic velocity. The secondary outcome was the increase of vessel diameter. For each hand, we obtained the differences of digital artery blood flows and diameters at baseline and after 60 minutes. Therefore, mean differences <0 indicated that the study cream was effective. Our findings are summarized in Tables I and II. Topical sildenafil significantly increased blood flow by 9.2 mm/sec (P < .0083), while a trend toward improvement was observed for diameter (P = .0695). After topical nifedipine, there was no significant improvement in blood flow or diameter. Five of 10 hands using nifedipine experienced sensation of heat and 6 of 10 hands with sildenafil developed a tingling sensation. No serious adverse effects were detected. Secondary RP is often refractory to standard therapies and is a therapeutic challenge. Current evidence supports the use of an oral calcium-channel blocker (eg, nifedipine) or synthetic prostacyclin analogue (iloprost), but substantial evidence is lacking for other agents.3Wigley F.M. Flavahan N.A. Raynaud’s phenomenon.N Engl J Med. 2016; 375: 556-565Crossref PubMed Scopus (165) Google Scholar There is limited evidence regarding the effectiveness of topical vasodilators for the management of RP. Only 1 study investigated the vasodilator effect of nifedipine gel on patients with RP, demonstrating an improvement of capillary circulation.4Foti C. Quaranta D. Pepe M.L. et al.Study on the effectiveness of a nifedipine gel for treatment of Raynaud’s phenomenon.J Biol Regul Homeost Agents. 2006; 20: 59-65PubMed Google Scholar No previous study has evaluated the efficacy of topical sildenafil. We found that 5% sildenafil cream improved the digital arterial blood flow in patients with secondary RP, suggesting local vasodilatation. A limitation was the small sample size. Although there was a brief washout period, the cohort ideally would have included patients naïve to vasodilators and with the same connective tissue disease. Additional studies are required to determine if 5% sildenafil cream reduce the frequency of RP flares. To our knowledge, this is the first study to suggest that topical sildenafil can significantly improve digital arterial blood flow in patients with secondary RP.Table IClinical characteristics of the study groupPatient no.SexAge, yDxMean disease duration of CTD, yMean disease duration from onset of RP, yTobacco smoker1F32Limited SSc23No2F65Limited SSc3035No3F49DM71No4F24SLE105No5F69Diffuse SSc34No6F35SLE1818No7F31Diffuse SSc12No8F46SLE314No9F44MCTD43No10F16DM44NoCTD, Connective tissue disease; DM, dermatomyositis; Dx, diagnosis; F, female; MCTD, mixed connective tissue disease; RP, Raynaud's phenomenon; SSc, systemic sclerosis; SLE, systemic lupus erythematosus. Open table in a new tab Table IIColor Doppler ultrasound characteristics of the study group before and after topical treatmentBeforeAfterDifferenceP valueSildenafil Doppler flow (PSV, mm/sec ± SD)32.1 ± 29.941.3 ± 35.2−9.2 ± 20.83.0083 Diameter, mm ± SD0.42 ± 0.330.50 ± 0.36−0.08 ± 0.26.0695Nifedipine Doppler flow (PSV, mm/sec ± SD)41.2 ± 44.542.6 ± 32.7−1.4 ± 37.5.808 Diameter, mm ± SD0.48 ± 0.380.48 ± 0.370 ± 0.241.0Control Doppler flow (PSV, mm/sec ± SD)38.2 ± 45.743.7 ± 32.8−5.5 ± 29.1.239 Diameter, mm ± SD0.42 ± 0.340.48 ± 0.27−0.06 ± 0.26.154PSV, Peak systolic velocity. Open table in a new tab CTD, Connective tissue disease; DM, dermatomyositis; Dx, diagnosis; F, female; MCTD, mixed connective tissue disease; RP, Raynaud's phenomenon; SSc, systemic sclerosis; SLE, systemic lupus erythematosus. PSV, Peak systolic velocity.