Sildenafil citrate therapy for pulmonary arterial hypertension.
BACKGROUND
Sildenafil inhibits phosphodiesterase type 5, an enzyme that metabolizes cyclic guanosine monophosphate, thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells, including those in the lung.


METHODS
In this double-blind, placebo-controlled study, we randomly assigned 278 patients with symptomatic pulmonary arterial hypertension (either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts) to placebo or sildenafil (20, 40, or 80 mg) orally three times daily for 12 weeks. The primary end point was the change from baseline to week 12 in the distance walked in six minutes. The change in mean pulmonary-artery pressure and World Health Organization (WHO) functional class and the incidence of clinical worsening were also assessed, but the study was not powered to assess mortality. Patients completing the 12-week randomized study could enter a long-term extension study.


RESULTS
The distance walked in six minutes increased from baseline in all sildenafil groups; the mean placebo-corrected treatment effects were 45 m (+13.0 percent), 46 m (+13.3 percent), and 50 m (+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively (P<0.001 for all comparisons). All sildenafil doses reduced the mean pulmonary-artery pressure (P=0.04, P=0.01, and P<0.001, respectively), improved the WHO functional class (P=0.003, P<0.001, and P<0.001, respectively), and were associated with side effects such as flushing, dyspepsia, and diarrhea. The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo. Among the 222 patients completing one year of treatment with sildenafil monotherapy, the improvement from baseline at one year in the distance walked in six minutes was 51 m.


CONCLUSIONS
Sildenafil improves exercise capacity, WHO functional class, and hemodynamics in patients with symptomatic pulmonary arterial hypertension.
Galiè
Nazzareno
N
Institute of Cardiology, University of Bologna, Bologna, Italy. n.galie@bo.nettuno.it
Ghofrani
Hossein A
HA
Torbicki
Adam
A
Barst
Robyn J
RJ
Rubin
Lewis J
LJ
Badesch
David
D
Fleming
Thomas
T
Parpia
Tamiza
T
Burgess
Gary
G
Branzi
Angelo
A
Grimminger
Friedrich
F
Kurzyna
Marcin
M
Simonneau
Gérald
G
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D004311:Double-Blind Method; D017079:Exercise Tolerance / Q000187:drug effects*; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D016896:Treatment Outcome; D016138:Walking
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases