BREATHE-5 was the first placebo-controlled trial to investigate the effects of bosentan (Tracleer®) in patients with Eisenmenger physiology (EP). EP is characterized by the development of pulmonary arterial hypertension (PAH) and consequent intracardiac right to left shunt and hypoxemia in patients with pre-existing congenital heart disease. EP has been regarded as not amenable to conventional treatments or surgery. Theoretically, some treatments may worsen the shunt and increase hypoxemia. Since EP is associated with increased endothelin expression, it has been hypothesized that patients may benefit from endothelin antagonism.
BREATHE-5 was a multi-center, randomized, double-blind, placebo-controlled study evaluating the effect of the dual endothelin receptor antagonist, bosentan on oxygen saturation (main primary objective, non-inferiority) and hemodynamics (second primary objective, superiority) in patients with WHO functional class III. Secondary objectives included exercise capacity, safety, and tolerability.
Fifty-four patients were randomized 2:1 to bosentan (n = 37) or placebo (n = 17). Baseline characteristics, including mean oxygen saturation (SpO2), mean pulmonary vascular resistance, indexed (PVRi) and 6-minute walk distance (6MWD), were comparable in both groups. After 16 weeks the treatment effect on SpO2 was 1.0% (95% CI = > -5, non-inferiority margin), demonstrating that bosentan did not worsen oxygen saturation. As this primary safety endpoint was reached, efficacy analyses were conducted. In comparison with placebo, PVRi was significantly reduced (treatment effect - 472 dyn.sec.cm-5; p=0.04) and exercise capacity, measured by the 6MWD was significantly increased (treatment effect + 34m; p=0.02). Four patients discontinued due to adverse events, two (5.4%) in the bosentan group and two (11.8%) in the placebo group. The bosentan safety profile was comparable to that observed in previous clinical trials in PAH.
In this first placebo-controlled trial in patients with EP, bosentan was well tolerated and improved exercise capacity and hemodynamics, without compromising peripheral oxygen saturation.
Bosentan may be an important new treatment option for patients with EP, a disease with poor prognosis.
Nazzareno Galiè, None.