Endothelin Receptor Antagonists for the Treatment of Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis

Table 3

Studies evaluating efficacy of endothelin receptor antagonists for systemic sclerosis-associated raynaud’s phenomenon and/or digital ulcers.

Author date	Study type	Intervention	Patients enrolled/; completed	Duration	Primary endpoint for assessment of RP and/or DU	Results
Korn et al. 2004; RAPIDS-1 [42]	R, PC, DB	(a) 62.5 mg bosentan BID × 4 weeks; 125 mg BID × 12 weeks; (b) Placebo BID × 16 weeks	(a) 79/66; (b) 43/37	16 weeks	Number of new DU developing during the 16-week study period.	Patients receiving bosentan had a 48% reduction in the mean number of new DU at the end of the treatment period (𝑃=0.0083). No difference between groups in the healing of existing ulcers.
Selenko-Gebaue et al. 2006 [43]	Obs	62.5 mg bosentan BID × 4 weeks; 125 mg BID × 12 weeks	3/3	16 weeks	RP activity and pain severity.	Pain, RP disease activity, number and severity of Raynaud’s attacks all decreased.
García dela Peña-Lefebne 2008 [44]	Obs	62.5 mg bosentan BID × 4 weeks; then 125 mg BID	15	4 to 36 months	Number and severity of DU.	There was a decrease in the number of DU. A trend towards efficacy was seen in the number of healed ulcers and in the severity of ulcers.
Funauchi et al. 2009 [45]	Obs	62.5 mg bosentan BID × 4 weeks; then 125 mg BID	15	40 to 96 weeks	Number and severity of DU and frequency and severity of RP.	After a median 8 weeks of treatment, 13 out of 15 patients had improved RP. DU also improved after a median 12 weeks' treatment in all of the 8 patients that had DU.
Tsifetaki et al. 2009 [46]	Obs	62.5 mg bosentan BID × 4 weeks; then 125 mg BID	26/23	36 months	Number of new and healed DU.	The mean number of DU per patient was reduced at 6, 12, and 36 months (𝑃<0.001).
Nguyen et al. 2010 [47]	R, PC, DB	(a) 62.5 mg bosentan BID × 4 weeks; 125 mg BID × 12 weeks; (b) Placebo BID × 16 weeks	(a) 9/8; (b) 8/8	16 weeks	RCS, frequency, duration, and pain associated with RP attacks.	Compared with placebo, bosentan did not significantly reduce the severity, frequency, duration, or pain of RP attacks.
Kuhn et al. 2010 [48]	Obs	62.5 mg bosentan BID × 4 weeks; 125 mg BID	10/8	24 weeks	Healing of current DU.	Bosentan increased the number of healed DU from 42% at baseline to 88% at week 24 (𝑃<0.0019).
Giordano et al. 2010 [49]	Obs	62.5 mg bosentan BID × 4 weeks; 125 mg BID	14/14	48 weeks	Number and duration of RP attacks	Number and duration of RP attacks showed a statistically significant decrease at 12 weeks and maintained through 24 and 48 weeks (𝑃<0.05).
Mattuci-Cerinic et al. 2011; RAPIDS-2 [50]	R, PC, DB	(a) 62.5 mg bosentan BID × 4 weeks; 125 mg BID × 20 weeks; (b) Placebo BID × 24 weeks	(a) 98/75; (b) 90/73	24 weeks	Number of new DU and the time to healing of a preexisting DU.	Bosentan treatment was associated with a 30% reduction in the number of new DU compared with placebo (𝑃=0.04). No difference between groups in healing rate of preexisting ulcers.

R: randomized, PC: placebo controlled, DB: double blind, Obs: observational, DU: digital ulcer, RP: Raynaud’s phenomenon, and RCS: Raynaud’s Condition Score.