PURPOSE: Preliminary data suggest that combination therapy with bosentan and sildenafil is efficacious and well tolerated. However, the pharmacodynamic basis of this combination has not been established. COMPASS-1, an open-label, uncontrolled, prospective, multi-center study, assessed the acute hemodynamic effects of sildenafil in pulmonary arterial hypertension (PAH) patients receiving bosentan therapy, showing a reduction in pulmonary vascular resistance (PVR). Here, we report a post-hoc analysis of the acute response to sildenafil in comparison with that to inhaled nitric oxide (iNO), a potent vasodilator, which was also evaluated in this study.
METHODS: PAH patients (≥ 18 years of age) on bosentan therapy (125 mg bid, for at least 12 weeks) were tested for acute vasoreactivity with iNO and subsequently received a single dose of sildenafil (25 mg) during right heart catheterization. PVR was measured before and after (5 minutes post-iNO, 60 minutes post-sildenafil) each intervention. In an exploratory analysis, the acute response (% change in PVR from pre- to post-intervention) to iNO vs sildenafil was compared in patients with complete PVR assessments.
RESULTS: Of 45 patients with PAH (80% idiopathic, 7% familial, 13% associated) enrolled in the study, 32 had complete PVR assessments. At catheterization, iNO lowered mean PVR (± SD) by 14.9% from 807±635 before to 745±740 dyne.s.cm-5 after inhalation (p<0.0001). Similarly, a reduction of 15.1% from 828±724 to 721±651 dyne.s.cm-5 was observed with sildenafil 60 minutes after intake (p<0.0001). The % change in PVR induced by iNO and sildenafil was similar. According to the European Society of Cardiology definition, one patient could be considered as having a positive acute vasodilator response to both interventions.
CONCLUSION: In PAH patients treated with bosentan, acute oral sildenafil reduced PVR significantly. The magnitude of the effect was similar to that observed with iNO.
CLINICAL IMPLICATIONS: These results suggest that either iNO or sildenafil can produce an acute additive pharmacodynamic effect when combined with bosentan therapy in PAH patients.
DISCLOSURE: Nazzareno Galie, No Product/Research Disclosure Information; Grant monies (from industry related sources) N. Galie has received grant support from Pfizer, Actelion, Schering, Encysive and Myogen; Consultant fee, speaker bureau, advisory committee, etc. N. Galie has sat on advisory boards for Pfizer, Actelion, Schering, Encysive, Myogen and Mondobiotech and has received lecture fees from Actelion and Schering.