AMSTERDAM, The Netherlands – The oral endothelin receptor antagonist bosentan (TracleerR, Actelion) cut the incidence of new digital ulcers in systemic sclerosis (SSc) patients by 38% and significantly improved several measures of cardiac function in clinical trials reported at the 2006 EULAR meeting.^1,2

James R. Seibold, MD, of the University of Michigan Scleroderma Program, Ann Arbor, Michigan, reported data from the RAPIDS I and II randomized, placebo-controlled trials of bosentan in SSc patients with at least one recent active digital ulcer (DU).1 Bosentan reduced the number of new ulcers but did not appear to promote healing.

"The treatment effect was strongest in patients at greatest risk, those with multiple previous digital ulcers, and there were also improvements in hand function," Dr. Seibold said. "The only confounder that seemed to blunt bosentan's effect was the persistence of smoking."

The 188 patients in this trial were randomized to placebo or to bosentan at 62.5 mg bid for 4 weeks then 125 mg bid for 20 to 32 weeks. DUs were assessed at four weekly intervals. The trial had two primary endpoints: time to complete healing of the cardinal ulcer and the total number of new DUs observed up to week 24.

The median new ulcers up to 24 weeks was 1.9 on bosentan vs 2.7 ± 0.3 on placebo (P = .035). The treatment effect was more pronounced in patients who had entered the trial with more than 3 active ulcers.

The other primary endpoint, time to healing, was not significantly affected by bosentan, and 50% of patients in each group still had persistence of the cardinal ulcer at 24 weeks, Dr. Seibold said. "It is important to note that nearly 70% of patients had at least one new ulcer during the trial, regardless of the treatment group they were assigned to."

Secondary endpoints included a number of important activities of daily living (ADL) measures, several of which were positively affected by bosentan. "SHAQ dressing improvement was significant for bosentan over PBO at 24 weeks (P = .033) and trended in favor of drug for eating at 24 weeks (P = .098). SHAQ Visual Analogue Scales improved on bosentan for pain at 12 weeks (P = .034)," Dr. Seibold reported.

Serious adverse effects were uncommon, but liver enzyme changes were noted more frequently with bosentan.

"This second large randomized, controlled trial confirms that bosentan reduces the number of new DUs in patients with SSc and that this effect is associated with reduced pain and improved hand function," Dr. Seibold concluded.

The second bosentan presentation was by Britannic Allanore, MD, of the Department of Rheumatology at Rene Descartes University in Paris. Dr. Allanore and colleagues used cardiac magnetic resonance imaging (MRI) and Doppler tissue imaging (DTI) to examine the effects of bosentan on myocardial perfusion and function in SSc patients.2

"Primary myocardial involvement due to microcirculation impairment is common in systemic sclerosis," Dr. Allanore said. "Endothelin is the strongest known endogenous vasoconstrictor and contributes to vascular dysfunction in SSc. Bosentan is a dual endothelin receptor antagonist, which previously demonstrated beneficial effects in SSc vascular complications such as pulmonary arterial hypertension and digital ulcers. The purpose of this study was to evaluate the short-term effects of bosentan on myocardial perfusion and function."

Dr. Allanore and colleagues prospectively evaluated 18 SSc patients who did not have clinical heart failure and who had normal pulmonary arterial pressure. They determined MRI perfusion index from time-intensity curves, and systolic and diastolic strain rates by DTI in the inferior wall at baseline (after a 72-hour vasodilator washout period ) and again after 4 weeks of bosentan (62.5 mg bid for 2 weeks titrated to 125 mg bid for 2 weeks).

At baseline the SSc patients had reduced MRI perfusion index, reduced systolic strain rates, and reduced diastolic strain rates. Following 4 weeks of bosentan, MRI perfusion index increased from 0.164 to 0.214 (P = .006), systolic strain rate increased from 2.17 to 3.02 (P = .0005), and diastolic strain rate increased from 2.85 to 3.77 (P = .0084).

"We also determined that this improvement was not due to changes in afterload," Dr. Allanore said.

The researchers concluded that short-term treatment with bosentan simultaneously improves myocardial perfusion and function in SSc. "We are now investigating whether a remodeling effect may take place with long-term treatment with bosentan," Dr. Allanore said.

Bosentan is currently approved to improve the exercise ability of patients with pulmonary arterial hypertension and carries a warning about the high risk of birth defects associated with taking the drug during pregnancy.

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