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Pulmonary arterial hypertension is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance, leading to right ventricular failure and premature death.1,2 Pathobiologic mechanisms of the disease include pulmonary endothelial dysfunction, which leads to impaired production of vasodilators, such as nitric oxide and prostacyclin, and overexpression of vasoconstrictors, such as endothelin-1.3,4 Treatment includes conventional agents (anticoagulants, diuretics, digoxin, and supplemental oxygen, as well as calcium-channel blockers in selected patients), vasodilators, and antiproliferative agents such as prostanoids and endothelin-receptor antagonists, which are targeted at abnormalities of endothelial function.5,6

Four agents are currently approved for the treatment of pulmonary arterial hypertension in the United States and Europe5: intravenous epoprostenol, the inhaled prostacyclin analogue iloprost, the subcutaneously and intravenously administered prostacyclin analogue treprostinil, and the oral endothelin-receptor antagonist bosentan. Although these drugs are efficacious, adverse effects in terms of safety, tolerability, drug delivery, or all of these factors occur with all of these agents.5,6 In addition, some medical therapy may fail in some patients in which case they may be considered for lung transplantation.7

Changes in nitric oxide pathways have been detected in patients with pulmonary arterial hypertension,8,9 and although inhaled nitric oxide is used for testing acute vasoreactivity,5,6 the long-term administration of this agent is cumbersome and requires a complex delivery system.10 The pulmonary vasodilating effects of nitric oxide11 are mediated through its second messenger, cyclic guanosine monophosphate (cGMP),12 which is rapidly degraded by phosphodiesterases. Phosphodiesterase type 5 is the predominant phosphodiesterase isoform in the lung that metabolizes cGMP,13 and it has been shown to be up-regulated in conditions associated with pulmonary hypertension.14,15 By selectively inhibiting phosphodiesterase type 5, sildenafil citrate (Revatio, Pfizer) promotes the accumulation of intracellular cGMP16 and thereby enhances nitric oxidemediated vasodilatation; it may also have antiproliferative effects on pulmonary vascular smooth-muscle cells.17 Initial studies involving animal models,14,18,19,20,21,22 data from open-label, uncontrolled trials involving patients with pulmonary arterial hypertension,23,24,25,26,27,28 and a small randomized, controlled study involving patients with idiopathic pulmonary arterial hypertension29 suggest that sildenafil is beneficial in the treatment of pulmonary arterial hypertension. The objectives of our double-blind, placebo-controlled clinical trial were to assess the efficacy and tolerability of three doses of sildenafil ― 20, 40, and 80 mg given orally three times daily ― in patients with pulmonary arterial hypertension.

Methods

Selection of Patients

Patients were included if they had pulmonary arterial hypertension (idiopathic, associated with connective-tissue disease, or occurring after surgical repair of congenital systemic-to-pulmonary shunts that had been performed at least five years previously). Pulmonary arterial hypertension was defined as a mean pulmonary-artery pressure of 25 mm Hg or more and a pulmonary-capillary wedge pressure of 15 mm Hg or less at rest. Study medication was added to the patient's conventional therapy. Treatment with intravenous epoprostenol, oral bosentan, intravenous or inhaled iloprost, or subcutaneous treprostinil and supplementation with L-arginine were prohibited. Patients with a six-minute walking distance of less than 100 m or more than 450 m were excluded. Local institutional review boards or independent ethics committees approved the protocol, and written informed consent was obtained from all patients.

Study Design

The initial study was a 12-week, double-blind, placebo-controlled trial conducted in 53 centers in the United States, Mexico, South America, Europe, Asia, Australia, South Africa, and Israel between October 2002 and November 2003. A stratified central-randomization scheme was used to assign patients to four treatment groups ― those receiving 20, 40, or 80 mg of sildenafil or placebo three times daily ― in a 1:1:1:1 ratio. The randomization was stratified with respect to the baseline walking distance (<325 m or 325 m) and cause of pulmonary arterial hypertension. Patients randomly assigned to 80 mg of sildenafil three times daily received 40 mg of sildenafil three times daily for the first seven days before the dose was escalated to 80 mg; patients randomly assigned to the other three treatment groups underwent dummy dose escalation after seven days.

All patients who completed the 12-week, double-blind study were eligible to enter a long-term extension study. Patients originally assigned to the groups receiving placebo, 20 mg of sildenafil, and 40 mg of sildenafil received 40 mg of sildenafil for the first six weeks of the extension study, and the dose was then increased to 80 mg of sildenafil. Patients originally assigned to receive 80 mg of sildenafil continued to receive that dose in the extension study but underwent dummy dose escalation at week 6 to maintain the blinding.

Outcome Measures

The primary measure of efficacy was the change in exercise capacity, as measured by the total distance walked in six minutes, from baseline to week 12.30 Other measures of efficacy were the changes in mean pulmonary-artery pressure, score on the Borg scale of dyspnea (with 0 representing no dyspnea and 10 maximal dyspnea), World Health Organization (WHO) functional classification of pulmonary arterial hypertension (an adaptation of the New York Heart Association classification),31 and time from randomization to clinical worsening (defined as death, transplantation, hospitalization for pulmonary arterial hypertension, or initiation of additional therapies for pulmonary arterial hypertension, such as intravenous epoprostenol or oral bosentan). Physical examinations and laboratory tests were performed, and investigators recorded adverse events throughout both studies.

Statistical Analysis

The database was retained by the sponsor, but the investigators had access to the complete database. The statistical analysis was performed by a statistician who is an employee of the sponsoring company; it was reviewed and approved by one of the academic authors, at the University of Washington, Seattle. The authors assume full responsibility for the completeness and accuracy of the content of the manuscript.

The primary end point was evaluated with the use of a sequential step-down, closed testing procedure,32,33,34 in which the mean response in each group receiving sildenafil was compared with that in the placebo group. The group receiving the highest dose of sildenafil (80 mg) was tested first, followed by the groups receiving 40 mg and 20 mg, provided that a significant benefit had been observed with the prior higher dose. If no significant benefit was observed in relation to a particular dose, then no further comparisons among doses were made. All pairwise comparisons for the primary end point were carried out at the prespecified two-sided alpha level of 0.01 with the use of a two-sample t-test, stratified for baseline walking distance and for categories according to cause. Assuming that there was a treatment effect from sildenafil of 55 m, as compared with placebo, and a standard deviation of 75 m, a sample of 60 patients per treatment group would provide 90 percent power to detect this difference at the two-sided alpha level of 0.01. With the allowance of a withdrawal rate of 12.5 percent after randomization, 275 patients were required for randomization.

The same sequential step-down testing procedure was used for analysis of the secondary end points, with pairwise comparisons performed at the two-sided alpha level of 0.05. Mean pulmonary-artery pressure was analyzed with the use of a stratified t-test; the time to clinical worsening was analyzed with the use of a stratified log-rank test (data for patients with no documentation of clinical worsening were included in the analysis as censored observations); the score on the Borg scale of dyspnea was analyzed with the use of a stratified Wilcoxon's rank-sum test; and the change in the WHO functional class from baseline to week 12 was analyzed with the use of logistic regression.

Intention-to-treat analyses were performed for all variables. To be included in the intention-to-treat analysis for the primary end point, the Borg dyspnea score, and the mean pulmonary-artery pressure, a patient must have received the study drug and had both a baseline and at least one post-baseline measurement of the specific end point. To be included in the intention-to-treat analysis for time to clinical worsening, a patient must have received the study drug. Missing data for assessments at week 12 were imputed with the use of the last-observation-carried-forward method.

A sensitivity analysis was performed, which included patients who had not had a baseline walking test (the baseline walking distance was imputed with the use of results from the patients' screening walking test) and patients with no assessments of walking distance after baseline. In this analysis, for patients for whom no assessments had been performed after baseline, the six-minute walking distance at week 12 was set to the baseline result; for patients who had died, the distance at week 12 was set to 0; and for all other patients, either the distance at week 12 or the last assessment that had been performed was carried forward. A per-protocol population analysis was also conducted.

Results

A total of 278 patients were randomly assigned to receive placebo (70 patients) or sildenafil in doses of 20 mg (69 patients), 40 mg (68 patients), or 80 mg (71 patients) three times daily (Figure 1); 277 of the randomized patients took at least one dose of the study medication.

  Figure 1. Numbers of Patients Enrolled in the 12-Week Study and in the Long-Term Extension Study Who Underwent Screening and Randomization.

The data cutoff for patients in the long-term extension study was February 4, 2005.

Baseline Characteristics

Baseline characteristics of the patients were similar among all four treatment groups (Table 1). Idiopathic pulmonary arterial hypertension was the most frequent diagnosis, and the predominant WHO functional classifications at baseline were class II (39 percent of patients) and class III (58 percent).

  Table 1. Baseline Characteristics of the Patients.

Exercise Capacity

An increase in the distance walked in six minutes was observed in all groups receiving sildenafil, as compared with placebo, at week 4, and this effect was maintained at weeks 8 and 12 (Figure 2). The mean placebo-corrected treatment effects among 266 patients at week 12 were 45 m among those receiving 20 mg of sildenafil (99 percent confidence interval, 21 to 70; P<0.001), 46 m for those receiving 40 mg (99 percent confidence interval, 20 to 72; P<0.001), and 50 m for those receiving 80 mg (99 percent confidence interval, 23 to 77; P<0.001). The sensitivity analysis that was performed with the use of alternative imputation methods for missing data corroborated the main analysis: the mean placebo-corrected treatment effects among 277 patients at week 12 were 38 m for those receiving 20 mg of sildenafil (99 percent confidence interval, 12 to 64; P<0.001), 45 m for those receiving 40 mg (99 percent confidence interval, 21 to 70; P<0.001), and 42 m for those receiving 80 mg (99 percent confidence interval, 9 to 75; P<0.001). The results from the per-protocol population analysis also confirmed the main analysis (P<0.001 for all three comparisons).

  Figure 2. Mean Changes from Baseline, with 95 Percent Confidence Intervals, in the Six-Minute Walking Distance at Week 12 in the Placebo and Sildenafil Groups.

With the use of a two-sample t-test stratified according to baseline walking distance and cause of pulmonary arterial hypertension, P<0.001 for the comparison of sildenafil in doses of 20, 40, and 80 mg with placebo. In this intention-to-treat analysis, 266 patients for whom outcome data were available were included. The dosing schedule for all study medication was three times daily.

Treatment Effects According to Subgroups

The treatment effect on the primary end point in each group receiving sildenafil was descriptively assessed for subgroups of patients that were defined according to demographic features, disease characteristics, and baseline variables (Figure 3). There was placebo-corrected improvement in the mean six-minute walking distance in all subgroups receiving sildenafil.

  Figure 3. Effect of Treatment on the Six-Minute Walking Distance from Baseline to Week 12 in Patient Subgroups.