Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension.
BACKGROUND
Inhalation of the stable prostacyclin analogue iloprost is being studied for treatment of pulmonary hypertension. The selective phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation.


OBJECTIVE
To evaluate the safety and effectiveness of oral sildenafil, alone and in combination with inhaled iloprost, for treatment of pulmonary hypertension.


METHODS
Randomized, controlled, open-label trial.


METHODS
Intensive care unit.


METHODS
30 patients with severe pulmonary arterial hypertension (n = 16), chronic thromboembolic pulmonary hypertension (n = 13), or pulmonary hypertension due to aplasia of the left pulmonary artery (n = 1), all classified as New York Heart Association class III or IV.


METHODS
All patients received inhaled nitric oxide and aerosolized iloprost (inhaled dose, 2.8 microg). They were then randomly assigned to receive 12.5 mg of oral sildenafil, 50 mg of sildenafil, 12.5 mg of sildenafil plus inhaled iloprost, or 50 mg of sildenafil plus inhaled iloprost.


METHODS
Systemic and pulmonary arterial pressure, pulmonary arterial occlusion pressure, cardiac output, central venous pressure, peripheral arterial oxygen saturation, and arterial and mixed venous blood gases were measured during right-heart catheterization by using a Swan-Ganz catheter.


RESULTS
In rank order of pulmonary vasodilatory potency (maximum reduction of pulmonary vascular resistance and increase in cardiac index), 50 mg of sildenafil plus iloprost was most effective, followed by 12.5 mg of sildenafil plus iloprost. Iloprost alone and 50 mg of sildenafil were almost equally effective but were less potent than the combination regimens, and the least potent treatments were 12.5 mg of sildenafil and nitric oxide. In patients who received 50 mg of sildenafil plus iloprost, the maximum change in pulmonary vasodilatory potency was -44.2% (95% CI, -49.5% to -38.8%), compared with -14.1% (CI, -19.1% to -9.2%) in response to nitric oxide. With administration of 50 mg of sildenafil plus iloprost, the area under the curve for reduction in pulmonary vasodilatory resistance surpassed that of administration of 50 mg of sildenafil alone and iloprost alone combined, the vasodilatory effect lasted longer than 3 hours, and systemic arterial pressure and arterial oxygenation were maintained. No serious adverse events occurred.


CONCLUSIONS
Although limited by the small sample and lack of long-term observations, the study shows that oral sildenafil is a potent pulmonary vasodilator that acts synergistically with inhaled iloprost to cause strong pulmonary vasodilatation in both severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.
Ghofrani
Hossein Ardeschir
HA
Department of Internal Medicine, University Hospital, Justus-Liebig-University, Klinikstrasse 36, 35392 Giessen, Germany. ardeschir.ghofrani@innere.med.uni-giessen.de
Wiedemann
Ralph
R
Rose
Frank
F
Olschewski
Horst
H
Schermuly
Ralph Theo
RT
Weissmann
Norbert
N
Seeger
Werner
W
Grimminger
Friedrich
F
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000704:Analysis of Variance; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D016285:Iloprost / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010879:Piperazines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014665:Vasodilator Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D016285:Iloprost