PURPOSE: The EARLY study assessed the efficacy and safety of bosentan in mildly symptomatic (WHO class II) pulmonary arterial hypertension (PAH) patients. A secondary objective was to test the impact of combination therapy by evaluating the benefit of bosentan in a predefined cohort of sildenafil-treated patients. This represents the first assessment of this drug combination in the context of a randomized, double-blind, placebo-controlled trial.
METHODS: Patients with PAH (idiopathic/associated with HIV/congenital heart disease/connective tissue disease; 6-minute walk distance [6-MWD] <80% predicted or <500m with a Borg index of ≥2 points) randomly received bosentan (62.5mg bid for 4 weeks, then 125mg bid) or placebo double-blind for 6 months. Sildenafil-treated patients were stratified at randomization. Predefined analyses were performed on primary (pulmonary vascular resistance [PVR] at Month 6 [% of baseline], change in 6-MWD) and secondary (time to clinical worsening) endpoints in subgroups with or without sildenafil treatment.
RESULTS: Of 185 patients enrolled, 29 were on sildenafil at baseline (14 bosentan, 15 placebo). Mean baseline PVR was higher in sildenafil-treated patients (1006 and 951dyn.sec/cm5 in bosentan and placebo groups, respectively) than in those not taking sildenafil (821 and 772dyn.sec/cm5, respectively). Respective 6-MWDs were similar in both subgroups (means ranging from 430 to 444m). At Month 6, a similar bosentan treatment effect on PVR was seen in both subgroups (-20%, P=0.0478 sildenafil; -23%, P<0.0001 no sildenafil). The median treatment effect on 6-MWD with bosentan compared with placebo in patients on and not on sildenafil was +5 and +15m, respectively (non-significant in both subgroups). Additionally, a delay in clinical worsening was observed with bosentan compared with placebo in both subgroups: hazard ratio (95% confidence limits): 0.345 (0.04,3.32) sildenafil; 0.193 (0.04,0.88) no sildenafil.
CONCLUSION: In mildly symptomatic, sildenafil-treated PAH patients, add-on bosentan therapy improved hemodynamics and suggests a delay in clinical worsening, consistent with the effects seen in patients not receiving concomitant sildenafil.
CLINICAL IMPLICATIONS: Bosentan appears to be a treatment option for mildly symptomatic PAH patients, both as monotherapy and in combination with sildenafil.
DISCLOSURE: Lewis Rubin, Grant monies (from industry related sources) LJ Rubin has received grants from Actelion (EARLY Study sub-investigator) and Pfizer (PACES); Consultant fee, speaker bureau, advisory committee, etc. LJ Rubin has received consultancy fees from Actelion and Pfizer; Product/procedure/technique that is considered research and is NOT yet approved for any purpose. Bosentan is not approved for use in WHO functional class II PAH patients.