Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension
Nazzareno Galiè, M.D., Hossein A. Ghofrani, M.D., Adam Torbicki, M.D., Robyn J. Barst, M.D., Lewis J. Rubin, M.D., David Badesch, M.D., Thomas Fleming, Ph.D., Tamiza Parpia, Ph.D., Gary Burgess, M.D., Angelo Branzi, M.D., Friedrich Grimminger, M.D., Marcin Kurzyna, M.D., Gérald Simonneau, M.D., for the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group
Background Sildenafil inhibits phosphodiesterase type 5, anenzyme that metabolizes cyclic guanosine monophosphate, therebyenhancing the cyclic guanosine monophosphate–mediatedrelaxation and growth inhibition of vascular smooth-muscle cells,including those in the lung.
Methods In this double-blind, placebo-controlled study, we randomlyassigned 278 patients with symptomatic pulmonary arterial hypertension(either idiopathic or associated with connective-tissue diseaseor with repaired congenital systemic-to-pulmonary shunts) toplacebo or sildenafil (20, 40, or 80 mg) orally three timesdaily for 12 weeks. The primary end point was the change frombaseline to week 12 in the distance walked in six minutes. Thechange in mean pulmonary-artery pressure and World Health Organization(WHO) functional class and the incidence of clinical worseningwere also assessed, but the study was not powered to assessmortality. Patients completing the 12-week randomized studycould enter a long-term extension study.
Results The distance walked in six minutes increased from baselinein all sildenafil groups; the mean placebo-corrected treatmenteffects were 45 m (+13.0 percent), 46 m (+13.3 percent), and50 m (+14.7 percent) for 20, 40, and 80 mg of sildenafil, respectively(P<0.001 for all comparisons). All sildenafil doses reducedthe 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 sideeffects such as flushing, dyspepsia, and diarrhea. The incidenceof clinical worsening did not differ significantly between thepatients treated with sildenafil and those treated with placebo.Among the 222 patients completing one year of treatment withsildenafil monotherapy, the improvement from baseline at oneyear in the distance walked in six minutes was 51 m.
Conclusions Sildenafil improves exercise capacity, WHO functionalclass, and hemodynamics in patients with symptomatic pulmonaryarterial hypertension.
Pulmonary arterial hypertension is defined as a group of diseasescharacterized by a progressive increase in pulmonary vascularresistance, leading to right ventricular failure and prematuredeath.1,2 Pathobiologic mechanisms of the disease include pulmonaryendothelial dysfunction, which leads to impaired productionof vasodilators, such as nitric oxide and prostacyclin, andoverexpression of vasoconstrictors, such as endothelin-1.3,4Treatment includes conventional agents (anticoagulants, diuretics,digoxin, and supplemental oxygen, as well as calcium-channelblockers in selected patients), vasodilators, and antiproliferativeagents 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 pulmonaryarterial hypertension in the United States and Europe5: intravenousepoprostenol, the inhaled prostacyclin analogue iloprost, thesubcutaneously and intravenously administered prostacyclin analoguetreprostinil, and the oral endothelin-receptor antagonist bosentan.Although these drugs are efficacious, adverse effects in termsof safety, tolerability, drug delivery, or all of these factorsoccur with all of these agents.5,6 In addition, some medicaltherapy may fail in some patients in which case they may beconsidered for lung transplantation.7
Changes in nitric oxide pathways have been detected in patientswith pulmonary arterial hypertension,8,9 and although inhalednitric oxide is used for testing acute vasoreactivity,5,6 thelong-term administration of this agent is cumbersome and requiresa complex delivery system.10 The pulmonary vasodilating effectsof nitric oxide11 are mediated through its second messenger,cyclic guanosine monophosphate (cGMP),12 which is rapidly degradedby phosphodiesterases. Phosphodiesterase type 5 is the predominantphosphodiesterase isoform in the lung that metabolizes cGMP,13and it has been shown to be up-regulated in conditions associatedwith pulmonary hypertension.14,15 By selectively inhibitingphosphodiesterase type 5, sildenafil citrate (Revatio, Pfizer)promotes the accumulation of intracellular cGMP16 and therebyenhances nitric oxide–mediated vasodilatation; it mayalso have antiproliferative effects on pulmonary vascular smooth-musclecells.17 Initial studies involving animal models,14,18,19,20,21,22data from open-label, uncontrolled trials involving patientswith pulmonary arterial hypertension,23,24,25,26,27,28 and asmall randomized, controlled study involving patients with idiopathicpulmonary arterial hypertension29 suggest that sildenafil isbeneficial in the treatment of pulmonary arterial hypertension.The objectives of our double-blind, placebo-controlled clinicaltrial were to assess the efficacy and tolerability of threedoses of sildenafil — 20, 40, and 80 mg given orally threetimes 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 occurringafter surgical repair of congenital systemic-to-pulmonary shuntsthat had been performed at least five years previously). Pulmonaryarterial hypertension was defined as a mean pulmonary-arterypressure of 25 mm Hg or more and a pulmonary-capillary wedgepressure of 15 mm Hg or less at rest. Study medication was addedto the patient's conventional therapy. Treatment with intravenousepoprostenol, oral bosentan, intravenous or inhaled iloprost,or subcutaneous treprostinil and supplementation with L-argininewere prohibited. Patients with a six-minute walking distanceof less than 100 m or more than 450 m were excluded. Local institutionalreview boards or independent ethics committees approved theprotocol, and written informed consent was obtained from allpatients.
Study Design
The initial study was a 12-week, double-blind, placebo-controlledtrial conducted in 53 centers in the United States, Mexico,South America, Europe, Asia, Australia, South Africa, and Israelbetween October 2002 and November 2003. A stratified central-randomizationscheme was used to assign patients to four treatment groups— those receiving 20, 40, or 80 mg of sildenafil or placebothree times daily — in a 1:1:1:1 ratio. The randomizationwas 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 timesdaily received 40 mg of sildenafil three times daily for thefirst seven days before the dose was escalated to 80 mg; patientsrandomly assigned to the other three treatment groups underwentdummy dose escalation after seven days.
All patients who completed the 12-week, double-blind study wereeligible to enter a long-term extension study. Patients originallyassigned to the groups receiving placebo, 20 mg of sildenafil,and 40 mg of sildenafil received 40 mg of sildenafil for thefirst six weeks of the extension study, and the dose was thenincreased to 80 mg of sildenafil. Patients originally assignedto receive 80 mg of sildenafil continued to receive that dosein the extension study but underwent dummy dose escalation atweek 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, frombaseline to week 12.30 Other measures of efficacy were the changesin mean pulmonary-artery pressure, score on the Borg scale ofdyspnea (with 0 representing no dyspnea and 10 maximal dyspnea),World Health Organization (WHO) functional classification ofpulmonary arterial hypertension (an adaptation of the New YorkHeart Association classification),31 and time from randomizationto clinical worsening (defined as death, transplantation, hospitalizationfor pulmonary arterial hypertension, or initiation of additionaltherapies for pulmonary arterial hypertension, such as intravenousepoprostenol or oral bosentan). Physical examinations and laboratorytests were performed, and investigators recorded adverse eventsthroughout both studies.
Statistical Analysis
The database was retained by the sponsor, but the investigatorshad access to the complete database. The statistical analysiswas performed by a statistician who is an employee of the sponsoringcompany; it was reviewed and approved by one of the academicauthors, at the University of Washington, Seattle. The authorsassume full responsibility for the completeness and accuracyof the content of the manuscript.
The primary end point was evaluated with the use of a sequentialstep-down, closed testing procedure,32,33,34 in which the meanresponse in each group receiving sildenafil was compared withthat in the placebo group. The group receiving the highest doseof sildenafil (80 mg) was tested first, followed by the groupsreceiving 40 mg and 20 mg, provided that a significant benefithad been observed with the prior higher dose. If no significantbenefit was observed in relation to a particular dose, thenno further comparisons among doses were made. All pairwise comparisonsfor the primary end point were carried out at the prespecifiedtwo-sided alpha level of 0.01 with the use of a two-sample t-test,stratified for baseline walking distance and for categoriesaccording to cause. Assuming that there was a treatment effectfrom sildenafil of 55 m, as compared with placebo, and a standarddeviation of 75 m, a sample of 60 patients per treatment groupwould provide 90 percent power to detect this difference atthe two-sided alpha level of 0.01. With the allowance of a withdrawalrate of 12.5 percent after randomization, 275 patients wererequired for randomization.
The same sequential step-down testing procedure was used foranalysis of the secondary end points, with pairwise comparisonsperformed at the two-sided alpha level of 0.05. Mean pulmonary-arterypressure was analyzed with the use of a stratified t-test; thetime to clinical worsening was analyzed with the use of a stratifiedlog-rank test (data for patients with no documentation of clinicalworsening were included in the analysis as censored observations);the score on the Borg scale of dyspnea was analyzed with theuse of a stratified Wilcoxon's rank-sum test; and the changein the WHO functional class from baseline to week 12 was analyzedwith 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 primaryend point, the Borg dyspnea score, and the mean pulmonary-arterypressure, a patient must have received the study drug and hadboth a baseline and at least one post-baseline measurement ofthe specific end point. To be included in the intention-to-treatanalysis for time to clinical worsening, a patient must havereceived the study drug. Missing data for assessments at week12 were imputed with the use of the last-observation-carried-forwardmethod.
A sensitivity analysis was performed, which included patientswho had not had a baseline walking test (the baseline walkingdistance was imputed with the use of results from the patients'screening walking test) and patients with no assessments ofwalking distance after baseline. In this analysis, for patientsfor whom no assessments had been performed after baseline, thesix-minute walking distance at week 12 was set to the baselineresult; for patients who had died, the distance at week 12 wasset to 0; and for all other patients, either the distance atweek 12 or the last assessment that had been performed was carriedforward. 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 onedose 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 amongall four treatment groups (Table 1). Idiopathic pulmonary arterialhypertension was the most frequent diagnosis, and the predominantWHO functional classifications at baseline were class II (39percent 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 observedin 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 among266 patients at week 12 were 45 m among those receiving 20 mgof 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 (99percent confidence interval, 23 to 77; P<0.001). The sensitivityanalysis that was performed with the use of alternative imputationmethods for missing data corroborated the main analysis: themean placebo-corrected treatment effects among 277 patientsat week 12 were 38 m for those receiving 20 mg of sildenafil(99 percent confidence interval, 12 to 64; P<0.001), 45 mfor those receiving 40 mg (99 percent confidence interval, 21to 70; P<0.001), and 42 m for those receiving 80 mg (99 percentconfidence interval, 9 to 75; P<0.001). The results fromthe per-protocol population analysis also confirmed the mainanalysis (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 groupreceiving sildenafil was descriptively assessed for subgroupsof patients that were defined according to demographic features,disease characteristics, and baseline variables (Figure 3).There was placebo-corrected improvement in the mean six-minutewalking 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.
The mean treatment effects, with 95 percent confidence intervals, are presented for each sildenafil dose. PAH denotes pulmonary arterial hypertension, CTD connective-tissue disease, S-P systemic-to-pulmonary, WHO World Health Organization, and PAP pulmonary-artery pressure. 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.
Borg Dyspnea Score
The change from baseline in scores on the Borg dyspnea scaleamong the patients treated with sildenafil did not differ significantlyfrom the change in the placebo group. The median Borg dyspneascore decreased (reflecting improvement) by 1 point among patientsreceiving 20 mg of sildenafil (95 percent confidence interval,–1 to 0), by 0 for those receiving 40 mg (95 percent confidenceinterval, –1 to 0), and by –1 for those receiving80 mg (95 percent confidence interval, –1.5 to 0), ascompared with placebo.
Hemodynamics
The patients receiving sildenafil had decreases from the baselinevalue in mean pulmonary-artery pressure and in pulmonary vascularresistance, as well as an increase in the cardiac index. Thesechanges differed significantly from those among the patientsreceiving placebo (Table 2).
Table 2. Mean Change in Hemodynamic Variables from Baseline to Week 12.
Clinical Worsening
No statistically significant decrease in the time to clinicalworsening or in the incidence of clinical worsening was observedwith sildenafil as compared with placebo (Table 3). An exploratoryanalysis showed that the proportion of hospitalizations forworsening of pulmonary arterial hypertension was greater inthe placebo group than in the combined sildenafil groups (P=0.02).
Table 3. Incidence of Clinical Worsening and of the Most Frequent Adverse Events in the Placebo and Sildenafil Groups.
WHO Functional Class
Data on the WHO functional class were available for 273 patients.After 12 weeks of double-blind treatment, the proportions ofpatients with an improvement of at least one functional classwere 7 percent for those receiving placebo, 28 percent for thosereceiving 20 mg of sildenafil (placebo-corrected difference,21 percent; 95 percent confidence interval, 9 to 33 percent;P=0.003), 36 percent for those receiving 40 mg (placebo-correcteddifference, 29 percent; 95 percent confidence interval, 16 to42 percent; P<0.001), and 42 percent for those receiving80 mg (placebo-corrected difference, 35 percent; 95 percentconfidence interval, 22 to 48 percent; P<0.001).
Long-Term Treatment
Of the 265 patients who completed the randomized 12-week study,259 entered the long-term prospective extension study, and 6declined enrollment (Figure 1). Patients who had been assignedto receive placebo and were then titrated up to 80 mg of sildenafilduring the first 12 weeks of the extension study (58 patients)had a mean increase from baseline in the six-minute walkingdistance of 42 m (95 percent confidence interval, 27 to 57 m)at week 12 of the extension.
Of the 259 patients enrolled in the extension study, 15 withdrewand 14 died before completing 12 months of treatment. As ofFebruary 4, 2005, 230 patients had been treated with sildenafilfor at least 12 months (median, 589 days; range, 400 to 844).Eight of the 230 patients received additional treatment (withprostanoids or endothelin-receptor antagonists) for pulmonaryarterial hypertension. An exploratory analysis was performedon the 222 patients receiving sildenafil monotherapy after 1year; after 12 weeks of treatment, the mean change from baselinein the six-minute walking distance was 48 m (95 percent confidenceinterval, 40 to 55); after 12 months, the mean change was 51m (95 percent confidence interval, 41 to 60).
Safety
Most adverse events were mild to moderate in intensity for alltreatment groups (Table 3). No clinically significant changeswere seen in any laboratory variables evaluated. Forty-two patientsreported 68 serious adverse events. However, only two seriousadverse events — left ventricular dysfunction in one patientreceiving 20 mg of sildenafil and postural hypotension in anotherpatient receiving an initial dose of 40 mg of sildenafil —were considered by the investigators to be related to the studymedication. The distribution and incidence of adverse eventswere similar among patients with different types of pulmonaryarterial hypertension, and the median times of first occurrencewere clustered within the first four to five weeks of treatment.
One patient in the placebo group died from right heart failure,and one in the group receiving 20 mg of sildenafil died fromacute pulmonary embolism and urosepsis. Two patients in thegroup receiving 80 mg of sildenafil died, one from acute myocardialinfarction and one from pneumonia while receiving 40 mg threetimes daily during the first seven days of the titration period.No death was judged by the investigators to be causally relatedto the study treatment. Eight patients withdrew from the randomized12-week study: two because of protocol violations, two becauseof withdrawal of consent, and four because of side effects (decreasedrenal function, lower-leg edema, cardiac arrhythmias, and headache).
Discussion
In this multicenter, randomized, double-blind, placebo-controlledtrial, sildenafil significantly improved exercise capacity,as assessed according to the six-minute walking test, in patientswith pulmonary arterial hypertension, whether it was idiopathicor related to connective-tissue disease or surgical repair ofcongenital systemic-to-pulmonary shunts. Our findings show thatthere is a symptomatic benefit associated with the inhibitionof phosphodiesterase type 5 in patients with pulmonary arterialhypertension. All subgroups that were assessed had an improvementin exercise capacity with sildenafil treatment, regardless ofdemographic 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 deathin patients with idiopathic pulmonary arterial hypertension35and has been used as the primary end point in most clinicaltrials involving patients with pulmonary arterial hypertension.5The treatment-related increase in walking distance of 45 to50 m observed in this study is similar to the increases observedwith the use of intravenous epoprostenol (47 m),36 inhaled iloprost(36 m),37 and oral bosentan (44 m)38 and is higher than theincrease seen with the use of subcutaneous treprostinil (16m).39
It should be emphasized that most patients in the present studyhad 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 pulmonaryarterial hypertension of WHO class III or IV) had the greatestimprovement in the six-minute walking distance. The extensionstudy suggests that the effect of sildenafil monotherapy onexercise capacity is maintained after one year of treatment.This open-label, prospective evaluation reinforces the clinicalsignificance of the exercise improvements observed in the 12-weekstudy.
Sildenafil also significantly improved cardiopulmonary hemodynamicsat 12 weeks, as compared with changes at 12 weeks in the placebogroup. The reductions in pulmonary-artery pressure and increasesin cardiac index were similar to those observed with intravenousepoprostenol36 and oral bosentan38 in smaller studies. Hemodynamicvariables are related to survival in patients with idiopathicpulmonary arterial hypertension,40 and the results of this studyconfirm the clinical relevance of the effects of sildenafil.It is not clear what mechanisms are involved in the hemodynamicimprovements seen in patients with pulmonary arterial hypertensionwho have predominantly fixed pulmonary vascular obstructivelesions.3 It has been suggested that there is possible reverseremodeling of pulmonary vascular changes with both prostanoidsand endothelin-receptor antagonists, on the basis of their antiproliferativeproperties,6 and this may also explain the effects seen withsildenafil.17
The incidence of clinical worsening was not significantly differentin the patients treated with sildenafil than in those treatedwith placebo. However, the overall incidence of clinical worseningin this study was low and may be related to the sizable cohortof patients with pulmonary arterial hypertension of WHO functionalclass II (39 percent) and to the short duration of the study(12 weeks). In fact, in our study, the overall incidence ofclinical worsening in the placebo group was 10 percent (Table 3)and was lower than that in the placebo group of the BosentanRandomized Trial of Endothelin Antagonist Therapy (BREATHE-1)study.38 In addition, in the BREATHE-1 study, a statisticallysignificant difference in the time to clinical worsening wasobserved after 16 weeks, not 12.38
With all doses of sildenafil, most adverse events were of mildto moderate severity, and there were no clinically significantchanges in laboratory variables. Complex delivery systems, significantside effects, or both, are associated with intravenous epoprostenol(e.g., catheter-related infections, sepsis, and pump malfunctions),36subcutaneous treprostinil (infusion-site pain),39 inhaled iloprost(multiple daily inhalations),37 and oral bosentan (abnormalitiesof hepatic function).38
There was no evidence of a dose–response relationshipassociated with the primary end point (exercise capacity) orwith tolerability in the 12-week study. The reason for thisphenomenon is not clear but may be related to the complete inhibitionof phosphodiesterase type 5 with the lowest dose.
Limitations of the study include the exclusion of certain patientpopulations with pulmonary arterial hypertension, such as patientsin whom the pulmonary arterial hypertension is associated withthe human immunodeficiency virus, patients with portal hypertension,and those with hypertension that is associated with uncorrectedcongenital systemic-to-pulmonary shunts. Additional studiesinvolving these subgroups of patients are needed.
In conclusion, this study demonstrates the efficacy and safetyof sildenafil in the treatment of patients with symptomaticpulmonary arterial hypertension. Our assessment of efficacywas limited to exercise capacity and hemodynamic measures, andthe study was not designed to address the important end pointof mortality.
Supported by Pfizer Global Research and Development, Sandwich,Kent, United Kingdom.
Dr. Galiè reports having served on the advisory boardsof Pfizer, Actelion, Schering, Encysive, Myogen, and Mondobiotechand having received lecture fees from Actelion and Scheringand grant support from Pfizer, Actelion, Schering, Encysive,and Myogen. Dr. Ghofrani reports having served on the advisoryboards of Pfizer, Actelion, Schering, and Altana Pharma andhaving received lecture fees from Pfizer, Actelion, Lung Rx,and Schering and grant support from Pfizer and the German ResearchFoundation. Dr. Torbicki reports having served on the advisoryboards of Pfizer, Encysive, and Mondobiotech and having receivedlecture fees from Actelion, Schering, and Myogen and grant supportfrom the Foundation for Polish Science. Dr. Barst reports havingserved on the advisory boards of Actelion, CoTherix, Encysive,INO Therapeutics, Pfizer, United Therapeutics, Myogen, and Medtronicand having received lecture fees from Pfizer, Actelion, CoTherix,Encysive, and INO Therapeutics and grant support from Pfizer,Myogen, United Therapeutics, Actelion, CoTherix, Encysive, INOTherapeutics, and Medtronic. Dr. Rubin reports having servedon the advisory boards of Pfizer, Actelion, Myogen, United Therapeutics,CoTherix, and Mondobiotech; having received lecture fees fromActelion and grant support from the National Heart, Lung, andBlood Institute, Pfizer, Actelion, United Therapeutics, andMyogen; and having served as an expert witness in diet-druglitigation. Dr. Badesch reports having served on the advisoryboards of Pfizer, Actelion, Myogen, United Therapeutics, CoTherix,and Encysive; having received lecture fees from Actelion andEncysive and grant support from Pfizer, Actelion, Myogen, Cotherix,and Encysive; and having served as an expert witness in diet-druglitigation. Dr. Fleming reports having served on the advisoryboard of Pfizer. Drs. Parpia and Burgess are employees of Pfizerand report having equity interest in Pfizer. Dr. Branzi reportshaving received grant support from Pfizer, Actelion, Schering,Encysive, and Myogen. Dr. Grimminger reports having served onthe advisory boards of Pfizer and Altana Pharma, and havingreceived lecture fees from Pfizer and Schering and grant supportfrom Pfizer, Bayer, Altana Pharma, and the German Research Foundation.Dr. Kurzyna reports having served as a consultant for Pfizerand having received lecture fees from Myogen. Dr. Simonneaureports having served on the advisory boards of Pfizer, Actelion,Schering, and Encysive, and having received lecture fees fromPfizer, Actelion, Encysive, and Schering and grant support fromPfizer, 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 Hôpital 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{at}bo.nettuno.it.
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A correction has been published: N Engl J Med 2006;354(22):2400.
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. 
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