Randomized Placebo-Controlled Crossover Trial of Tadalafil in Raynaud's Phenomenon Secondary to Systemic Sclerosis

Abstract

Conclusion: Tadalafil is well tolerated and safe in patients with systemic sclerosis but lacks efficacy in comparison with placebo. Summary: The endothelial injury of systemic sclerosis is associated with decreased nitric oxide production (Kahaleh et al, Rheum Diseases Clin N Am 2008;34:57-71). Type V cyclic GMP phosphodiesterase (PDE-5) affects the tone of smooth muscle. An intracellular regulator of smooth muscle tone is cyclic nucleotide monophosphate, cGMP. Nitric oxide synthase produces nitric oxide. Through a complex pathway, nitric oxide facilitates conversion of GTP into cGMP. PDE-5 breaks down intracellular cGMP. Therefore, inhibition of PDE-5 results in increased availability of intracellular cGMP and results in vasodilatation. Tadalafil is a PDE-5 inhibitor effective in the use of male erectile dysfunction. However, PDE-5 inhibitors have also been suggested as beneficial in patients with severe Raynaud's syndrome (Fries R et al, Circulation 2005;119:2980-5). Tadalafil is an intriguing PDE-5 inhibitor in that it has a half-life of 17.5 hours and efficacy up to 36 hours. The pharmacokinetics of tadalafil are not affected by food or alcohol, age, diabetes, or moderate hepatic insufficiency. It therefore would seem an ideal drug for facilitating vasodilatation in patients with Raynaud's syndrome. This was a randomized, prospective, double-blind, placebo-controlled, crossover study comparing oral tadalafil with a fixed daily dose of 20 mg for 4 weeks vs placebo. The study was conducted in patients with Raynaud's syndrome secondary to systemic sclerosis. Thirty-nine completed the study. All patients fulfilled American College of Rheumatology classification criteria for systemic sclerosis. All were at least 18 years of age and had evidence of at least six Raynaud's attacks during the 2-week pretreatment period. Patients with unstable angina, congestive heart failure, or use of nitrites for angina pectoris or any other condition as well as those with significant central nervous system disease were excluded. Before enrollment, all patients discontinued any other type of vasodilator. Patients were evaluated for duration and frequency of Raynaud's attacks and Raynaud condition scores (RCS). At the end of the evaluation period, there were no significant statistical differences in RCS scores, frequency of Raynaud's attacks, or duration of Raynaud's attacks between the treatment and placebo groups. Comment: The results of the study are disappointing but not conclusive. The participants in this trial had a longer duration of Raynaud's syndrome than those in other trials. Severity of Raynaud's syndrome secondary to systemic sclerosis often increases over time. Patients here may have had greater endothelial cumulative damage than those in other studies. Other studies have primarily evaluated the effect of PDE-5 inhibitors on ulcer healing. Only two patients in this study had active digital ulcers. However, overall, the current results do not support the use of tadalafil as treatment for Raynaud's syndrome secondary to systemic sclerosis at the dosage of 20 mg/d. The study was also burdened by a large placebo effect.