Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: results of the COMPASS-1 study.
This study investigated the acute pharmacodynamic effects of sildenafil in patients with pulmonary arterial hypertension (PAH) and concomitant bosentan treatment, in view of a mutual pharmacokinetic interaction between the 2 drugs. This prospective, open-label, noncomparative, multicenter, phase II study enrolled 45 patients (>or=18 years) with stable PAH (idiopathic, familial, or related to corrected congenital systemic-to-pulmonary shunts, drugs, or toxins) and on bosentan treatment for at least 3 months. Patients underwent right heart catheterization to evaluate the acute hemodynamic effects of (a) inhaled nitric oxide (iNO) and (b) a single oral dose of sildenafil (25 mg). Mean pulmonary vascular resistance (PVR) decreased from baseline following iNO (-15%; 95% confidence limits: -21%, -8%; P = .0001). A statistically significant decrease from baseline in mean PVR was also observed 60 minutes following sildenafil administration (-15%; 95% confidence limits: -21%, -10%; P < .0001). The reduction in PVR following sildenafil was comparable to that resulting from iNO. There were no unexpected safety findings. The pharmacodynamic effect suggests that addition of sildenafil to bosentan treatment can elicit additional hemodynamic benefits. These data represent a rationale for long-term combination studies with the 2 compounds.
Gruenig
Ekkehard
E
University Hospital, Heidelberg, Germany. ekkehard.gruenig@thoraxklinik-heidelberg.de
Michelakis
Evangelos
E
Vachiéry
Jean-Luc
JL
Vizza
Carmine Dario
CD
Meyer
F Joachim
FJ
Doelberg
Martin
M
Bach
Doris
D
Dingemanse
Jasper
J
Galiè
Nazzareno
N
D000959:Antihypertensive Agents / Q000008:administration & dosage; D000077300:Bosentan; D004347:Drug Interactions; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D008955:Models, Cardiovascular; D009569:Nitric Oxide / Q000494:pharmacology; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage*; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*
D000959:Antihypertensive Agents; D010879:Piperazines; D011687:Purines; D013449:Sulfonamides; D013450:Sulfones; D014665:Vasodilator Agents; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D000077300:Bosentan