Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension.
BACKGROUND
Inhaled treprostinil was recently developed for the treatment of pulmonary arterial hypertension (PAH). We investigated the safety and acute haemodynamic effects of the combination oral sildenafil and inhaled treprostinil in an open label study in patients with precapillary pulmonary hypertension.


METHODS
Inhaled nitric oxide (20ppm; n=50), sildenafil (50mg; n=50) and inhaled treprostinil (15microg; n=25 or 30microg; n=25) were applied in subsequent order during right heart catheter investigation to consecutive patients with pulmonary arterial hypertension (PAH; n=28), non-operable chronic thromboembolic pulmonary hypertension (CTEPH; n=17) and pulmonary fibrosis associated pulmonary hypertension (n=5).


RESULTS
Inhaled nitric oxide reduced pulmonary vascular resistance (PVR) to 87.3+/-5.1% of baseline values, reduced mean pulmonary arterial pressure (PAP) to 89.7+/-3.5% and increased cardiac output (CO) to 102.4+/-2.9%. Sildenafil reduced PVR to 80.1+/-5.0%, mPAP to 86.5+/-2.9% and increased CO to 103.8+/-3.2%. Treprostinil, inhaled 1h after sildenafil, reduced PVR to 66.3+/-3.8%, mPAP to 77.8+/-3.3%, and increased CO to 107.1+/-3.3% (mean+/-95% confidence interval). Subgroup analysis showed similar acute haemodynamic effects in PAH and CTEPH patients. Ventilation/perfusion distribution measurement in six patients with pre-existing gas exchange limitations was not changed by sildenafil and treprostinil. Relevant side effects were not observed.


CONCLUSIONS
The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients. This could be of relevance also for long-term treatment of PAH and CTEPH patients.
Voswinckel
Robert
R
Department of Internal Medicine, University of Giessen Lung Center, University Hospital Giessen and Marburg GmbH, Giessen, Germany. robert.voswinckel@innere.med.uni-giessen.de
Reichenberger
Frank
F
Enke
Beate
B
Kreckel
Andre
A
Krick
Stefanie
S
Gall
Henning
H
Schermuly
Ralph Theo
RT
Grimminger
Friedrich
F
Rubin
Lewis J
LJ
Olschewski
Horst
H
Seeger
Werner
W
Ghofrani
Hossein A
HA
D000280:Administration, Inhalation; D000284:Administration, Oral; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D003371:Cough / Q000139:chemically induced; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D011464:Epoprostenol / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D011659:Pulmonary Gas Exchange / Q000187:drug effects*; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D014655:Vascular Resistance / Q000187:drug effects
D000959:Antihypertensive Agents; D058986:Phosphodiesterase 5 Inhibitors; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D011464:Epoprostenol; C427248:treprostinil