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One patient in the placebo group died from right heart failure, and one in the group receiving 20 mg of sildenafil died from acute pulmonary embolism and urosepsis. Two patients in the group receiving 80 mg of sildenafil died, one from acute myocardial infarction and one from pneumonia while receiving 40 mg three times daily during the first seven days of the titration period. No death was judged by the investigators to be causally related to the study treatment. Eight patients withdrew from the randomized 12-week study: two because of protocol violations, two because of withdrawal of consent, and four because of side effects (decreased renal function, lower-leg edema, cardiac arrhythmias, and headache).

Discussion

In this multicenter, randomized, double-blind, placebo-controlled trial, sildenafil significantly improved exercise capacity, as assessed according to the six-minute walking test, in patients with pulmonary arterial hypertension, whether it was idiopathic or related to connective-tissue disease or surgical repair of congenital systemic-to-pulmonary shunts. Our findings show that there is a symptomatic benefit associated with the inhibition of phosphodiesterase type 5 in patients with pulmonary arterial hypertension. All subgroups that were assessed had an improvement in exercise capacity with sildenafil treatment, regardless of demographic or disease characteristics or other baseline variables. The study was not designed to assess mortality.

The six-minute walking test is an independent predictor of death in patients with idiopathic pulmonary arterial hypertension35 and has been used as the primary end point in most clinical trials involving patients with pulmonary arterial hypertension.5 The treatment-related increase in walking distance of 45 to 50 m observed in this study is similar to the increases observed with the use of intravenous epoprostenol (47 m),36 inhaled iloprost (36 m),37 and oral bosentan (44 m)38 and is higher than the increase seen with the use of subcutaneous treprostinil (16 m).39

It should be emphasized that most patients in the present study had pulmonary arterial hypertension of WHO class II or III, representing a less sick population than in the other studies. In those trials, the sickest patients (those with pulmonary arterial hypertension of WHO class III or IV) had the greatest improvement in the six-minute walking distance. The extension study suggests that the effect of sildenafil monotherapy on exercise capacity is maintained after one year of treatment. This open-label, prospective evaluation reinforces the clinical significance of the exercise improvements observed in the 12-week study.

Sildenafil also significantly improved cardiopulmonary hemodynamics at 12 weeks, as compared with changes at 12 weeks in the placebo group. The reductions in pulmonary-artery pressure and increases in cardiac index were similar to those observed with intravenous epoprostenol36 and oral bosentan38 in smaller studies. Hemodynamic variables are related to survival in patients with idiopathic pulmonary arterial hypertension,40 and the results of this study confirm the clinical relevance of the effects of sildenafil. It is not clear what mechanisms are involved in the hemodynamic improvements seen in patients with pulmonary arterial hypertension who have predominantly fixed pulmonary vascular obstructive lesions.3 It has been suggested that there is possible reverse remodeling of pulmonary vascular changes with both prostanoids and endothelin-receptor antagonists, on the basis of their antiproliferative properties,6 and this may also explain the effects seen with sildenafil.17

The incidence of clinical worsening was not significantly different in the patients treated with sildenafil than in those treated with placebo. However, the overall incidence of clinical worsening in this study was low and may be related to the sizable cohort of patients with pulmonary arterial hypertension of WHO functional class II (39 percent) and to the short duration of the study (12 weeks). In fact, in our study, the overall incidence of clinical worsening in the placebo group was 10 percent (Table 3) and was lower than that in the placebo group of the Bosentan Randomized Trial of Endothelin Antagonist Therapy (BREATHE-1) study.38 In addition, in the BREATHE-1 study, a statistically significant difference in the time to clinical worsening was observed after 16 weeks, not 12.38

With all doses of sildenafil, most adverse events were of mild to moderate severity, and there were no clinically significant changes in laboratory variables. Complex delivery systems, significant side effects, or both, are associated with intravenous epoprostenol (e.g., catheter-related infections, sepsis, and pump malfunctions),36 subcutaneous treprostinil (infusion-site pain),39 inhaled iloprost (multiple daily inhalations),37 and oral bosentan (abnormalities of hepatic function).38

There was no evidence of a doseresponse relationship associated with the primary end point (exercise capacity) or with tolerability in the 12-week study. The reason for this phenomenon is not clear but may be related to the complete inhibition of phosphodiesterase type 5 with the lowest dose.

Limitations of the study include the exclusion of certain patient populations with pulmonary arterial hypertension, such as patients in whom the pulmonary arterial hypertension is associated with the human immunodeficiency virus, patients with portal hypertension, and those with hypertension that is associated with uncorrected congenital systemic-to-pulmonary shunts. Additional studies involving these subgroups of patients are needed.

In conclusion, this study demonstrates the efficacy and safety of sildenafil in the treatment of patients with symptomatic pulmonary arterial hypertension. Our assessment of efficacy was limited to exercise capacity and hemodynamic measures, and the study was not designed to address the important end point of mortality.

Supported by Pfizer Global Research and Development, Sandwich, Kent, United Kingdom.

Dr. Galiè reports having served on the advisory boards of Pfizer, Actelion, Schering, Encysive, Myogen, and Mondobiotech and having received lecture fees from Actelion and Schering and grant support from Pfizer, Actelion, Schering, Encysive, and Myogen. Dr. Ghofrani reports having served on the advisory boards of Pfizer, Actelion, Schering, and Altana Pharma and having received lecture fees from Pfizer, Actelion, Lung Rx, and Schering and grant support from Pfizer and the German Research Foundation. Dr. Torbicki reports having served on the advisory boards of Pfizer, Encysive, and Mondobiotech and having received lecture fees from Actelion, Schering, and Myogen and grant support from the Foundation for Polish Science. Dr. Barst reports having served on the advisory boards of Actelion, CoTherix, Encysive, INO Therapeutics, Pfizer, United Therapeutics, Myogen, and Medtronic and having received lecture fees from Pfizer, Actelion, CoTherix, Encysive, and INO Therapeutics and grant support from Pfizer, Myogen, United Therapeutics, Actelion, CoTherix, Encysive, INO Therapeutics, and Medtronic. Dr. Rubin reports having served on the advisory boards of Pfizer, Actelion, Myogen, United Therapeutics, CoTherix, and Mondobiotech; having received lecture fees from Actelion and grant support from the National Heart, Lung, and Blood Institute, Pfizer, Actelion, United Therapeutics, and Myogen; and having served as an expert witness in diet-drug litigation. Dr. Badesch reports having served on the advisory boards of Pfizer, Actelion, Myogen, United Therapeutics, CoTherix, and Encysive; having received lecture fees from Actelion and Encysive and grant support from Pfizer, Actelion, Myogen, Cotherix, and Encysive; and having served as an expert witness in diet-drug litigation. Dr. Fleming reports having served on the advisory board of Pfizer. Drs. Parpia and Burgess are employees of Pfizer and report having equity interest in Pfizer. Dr. Branzi reports having received grant support from Pfizer, Actelion, Schering, Encysive, and Myogen. Dr. Grimminger reports having served on the advisory boards of Pfizer and Altana Pharma, and having received lecture fees from Pfizer and Schering and grant support from Pfizer, Bayer, Altana Pharma, and the German Research Foundation. Dr. Kurzyna reports having served as a consultant for Pfizer and having received lecture fees from Myogen. Dr. Simonneau reports having served on the advisory boards of Pfizer, Actelion, Schering, and Encysive, and having received lecture fees from Pfizer, Actelion, Encysive, and Schering and grant support from Pfizer, Actelion, Schering, and Encysive.

Source Information

From the Institute of Cardiology, University of Bologna, Bologna, Italy (N.G., A.B.); University Hospital, Justus-Liebig-University, Giessen, Germany (H.A.G., F.G.); the Institute of Tuberculosis and Lung Disease, Warsaw, Poland (A.T., M.K.); Babies and Children's Hospital, Columbia Presbyterian Medical Center, New York (R.J.B.); the University of California at San Diego, La Jolla (L.J.R.); University of Colorado Health Sciences Center, Denver (D.B.); the University of Washington, Seattle (T.F.); Pfizer Global Research and Development, Sandwich, Kent, United Kingdom (T.P., G.B.); and H?pital Antoine Béclère, Clamart, France (G.S.).

Address reprint requests to Dr. Galiè at the Institute of Cardiology, University of Bologna, Via Massarenti, 9, 40138 Bologna, Italy, or at n.galie@bo.nettuno.it.

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