Caglayan E, Axmann S, Hellmich M, Moinzadeh P, Rosenkranz S. Vardenafil for the treatment of Raynaud phenomenon: a randomized, double-blind, placebocontrolled crossover study. Arch Intern Med. Published online June 18, 2012. doi:10.1001/archinternmed.2012.2271
eAppendix. Supplemental methods
eTable. Baseline demographics
eFigure 1. CONSORT flow diagram
eFigure 2. Trend of the Raynaud condition score (RCS) during the course of the study
This supplementary material has been provided by the authors to give readers additional information about their work.
Caglayan E, Axmann S, Hellmich M, Moinzadeh P, Rosenkranz S. Vardenafil for the Treatment of Raynaud Phenomenon: A Randomized, Double-blind, Placebo-Controlled Crossover Study. Arch Intern Med. 2012;172(15):1182-1184. doi:10.1001/archinternmed.2012.2271
Author Affiliations: Klinik III für Innere Medizin (Drs Caglayan and Rosenkranz and Ms Axmann), Institut für Medizinische Statistik, Informatik und Epidemiologie (Dr Hellmich), and Klinik und Poliklinik für Dermatologie (Dr Moinzadeh), Universität zu Köln, Köln, Germany.
Raynaud phenomenon (RP) is common and occurs with severe symptoms, particularly in patients with connective tissue disease (CTD), in whom RP may lead to digital ulcerations and amputations.1,2 Medical therapy in these patients remains unsatisfactory. Administration of phosphodiesterase type 5 (PDE5) inhibitors, which inhibit the degradation of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells, promote vasorelaxation and are a promising therapeutic approach. However, randomized controlled trials have yielded conflicting results.3 We previously had conducted an open-label study with vardenafil hydrochloride trihydrate in patients with RP as a proof of concept.4 Our objective was to confirm our findings in a double-blind, randomized, placebo-controlled trial.
Patients with primary and secondary RP without active digital ulcers were recruited from the outpatient clinics of the Departments of Dermatology and Angiology at the University Hospital Cologne, from January 2006 through August 2009. We performed a double-blind, single-center, randomized, placebo-controlled, 2-period crossover study for 6 weeks to assess the efficacy and safety of vardenafil (10 mg twice daily) for the treatment of RP. Treatments were switched after a 1-week washout phase. Patients were followed up to 4 weeks after the last drug intake. All vasoactive agents were discontinued at least 1 week before study entry. Inclusion and exclusion criteria can be reviewed in detail online (http://clinicalsite.org/zks-koeln/en/trial/490). The study was approved by the Ethics Committee of the Medical Faculty of the University of Cologne. Primary outcomes were changes in the Raynaud condition score (RCS), which was assessed daily by a standardized patient questionnaire, and digital blood flow, measured by the use of a laser Doppler perfusion imager, as previously described.4 Secondary end points were safety and tolerability. Statistical analyses were performed according to the intention-to-treat (eFigure 1) using the software IBM SPSS Statistics 19 (SPSS Inc). P < .05 was considered statistically significant. Supplemental methods are available online (eAppendix).
Vardenafil significantly reduced the RCS on average by −0.45 compared with placebo (P = .03) and decreased the number (−0.51 vs placebo; P = .005) and cumulative duration (−11.43 minutes vs placebo; P = .003) of Raynaud attacks per day. The improvement of clinical symptoms by vardenafil was associated with a nonsignificant improved digital blood flow (+0.04 vs placebo; P = .14). Subgroup analyses revealed an increased efficacy of vardenafil in patients with primary RP and secondary RP with limited cutaneous systemic scleroderma compared with other subsets of patients with secondary RP (Table). Interestingly, in patients receiving vardenafil first, the RCS remained low during the washout phase and the entire second phase of the study when patients received placebo, suggesting a prolonged drug effect (eFigure 2). However, statistical testing for a carryover effect did not yield significant results.
The majority of the patients were female (42 of 53 [79%]). Of the 53 patients, 47 (89%) had secondary RP, mainly due to systemic sclerosis, and 6 (11%) had primary RP (eTable).
Adverse events were notably more prevalent with vardenafil treatment and included flush symptoms (12 vs 2; P = .01), headache (14 vs 7; P = .19), dyspepsia (7 vs 1; P = .07), dizziness (9 vs 2; P = .07), nasal stuffiness (7 vs 1; P = .07), and visual abnormalities (4 vs 3; P > .99). Serious adverse events occurred in 1 patient receiving vardenafil and 2 patients receiving placebo and were not considered to be related to study drug intake and resolved completely.
This study is, to our knowledge, the largest randomized controlled trial investigating the efficacy and safety of a PDE5 inhibitor in patients with RP. The findings demonstrate that vardenafil is safe and improves clinical symptoms in these patients. The results are in line with our previous study and 2 other RCTs in patients with RP receiving sildenafil or tadalafil.4- 6 On the other hand, one study with a 4-week tadalafil therapy in a similar patient population failed to show efficacy, mainly owing to a placebo response.3 While we also observed a certain placebo response, a significant improvement was present in patients receiving vardenafil. Although representing an established tool in the assessment of RP, the RCS may appear subjective to some extent. The minimally important difference estimates for RCS are considered 1.4 to 1.5 points for improvement on a 0 to 10 visual analog scale in patients with active RP.7 The mean net RCS reduction at week 6 in our study compared with baseline was −1.07 in patients receiving vardenafil.
Because of the short plasma half-life of vardenafil (t1/2, approximately 4 h), it was surprising that its effect on clinical symptoms persisted throughout the washout phase and even beyond. Prolonged functional effects of PDE5 inhibitors, which exceed their plasma half-life, have also been found by others.5,8 The fact that a single-dose of a PDE5 inhibitor is insufficient to increase digital blood flow or attenuate cold-induced vasoconstriction in patients with RP indicates that the beneficial effect may involve mechanisms other than pure inhibition of cold-induced vasoconstriction.9
In conclusion, vardenafil appears safe and effective in improving clinical symptoms and digital blood flow in patients with RP. Surprisingly, clinical efficacy is prolonged after discontinuation of the drug.
Correspondence: Dr Caglayan, Klinik III für Innere Medizin, Universität zu Köln, Kerpener Str 62, 50937 Köln, Germany (email@example.com).
Published Online: June 18, 2012. doi:10.1001/archinternmed.2012.2271
Author Contributions: Dr Caglayan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Caglayan, Hellmich, and Rosenkranz. Acquisition of data: Caglayan, Axmann, and Moinzadeh. Analysis and interpretation of data: Caglayan, Hellmich, and Rosenkranz. Drafting of the manuscript: Caglayan, Axmann, Hellmich, and Rosenkranz. Critical revision of the manuscript for important intellectual content: Caglayan, Hellmich, Moinzadeh, and Rosenkranz. Statistical analysis: Hellmich. Obtained funding: Rosenkranz. Administrative, technical, and material support: Caglayan, Moinzadeh, and Rosenkranz. Study supervision: Caglayan and Rosenkranz. Ms Axmann and Dr Moinzadeh assisted in the recruitment (Ms Axmann) and investigation (Dr Moinzadeh) of patients.
Financial Disclosure: None reported.
Funding/Support: This study was funded by Bayer Healthcare, Leverkusen, Germany, who provided the study medication and also in part by the German Federal Ministry of Research and Education (BMBF grant 01KN0706). We kindly acknowledge support by ZKS Köln (grant BMBF 01KN1106).
Role of the Sponsors: The sponsor had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript.
Additional Contributions: Michael Huntgeburth, MD, contributed significantly to the study concept and design; Erland Erdmann, MD, Thomas Krieg, MD, and Nicolas Hunzelmann, MD, critically revised the manuscript for important intellectual content and provided administrative support.