Bosentan Therapy for Pulmonary Arterial Hypertension
Lewis J. Rubin, M.D., David B. Badesch, M.D., Robyn J. Barst, M.D., Nazzareno Galiè, M.D., Carol M. Black, M.D., Anne Keogh, M.D., Tomas Pulido, M.D., Adaani Frost, M.D., Sébastien Roux, M.D., Isabelle Leconte, Ph.D., Michael Landzberg, M.D., Gérald Simonneau, M.D., for the Bosentan Randomized Trial of Endothelin Antagonist Therapy Study Group
Background Endothelin-1 is a potent vasoconstrictor and smooth-musclemitogen. In a preliminary study, the orally administered dualendothelin-receptor antagonist bosentan improved exercise capacityand cardiopulmonary hemodynamics in patients with pulmonaryarterial hypertension. The present trial investigated the effectof bosentan on exercise capacity in a larger number of patientsand compared two doses.
Results At week 16, patients treated with bosentan had an improved six-minute walking distance;the mean difference between theplacebo group and the combined bosentan groups was 44 m (95percent confidence interval, 21 to 67; P<0.001). Bosentanalso improved the Borg dyspnea index and WHO functional classand increased the time to clinical worsening.
Conclusions The endothelin-receptor antagonist bosentan is beneficialin patients with pulmonary arterial hypertension and is welltolerated at a dose of 125 mg twice daily. Endothelin-receptorantagonism with oral bosentan is an effective approach to therapyfor pulmonary arterial hypertension.
There is increasing evidence that endothelin-1 has a pathogenicrole in pulmonary arterial hypertension10 and that blockadeof endothelin receptors may be beneficial.11 Endothelin-1 isa potent endogenous vasoconstrictor and smooth-muscle mitogenthat is overexpressed in the plasma and lung tissue of patientswith primary pulmonary hypertension12,13 and scleroderma.14Its actions are mediated by two receptors, ETA and ETB. In aprevious 12-week trial involving patients with pulmonary arterialhypertension (either primary or associated with scleroderma)who were in World Health Organization (WHO) functional classIII (defined as having symptoms with mild exertion), bosentan,an oral antagonist of both endothelin receptors, improved exercisecapacity and cardiopulmonary hemodynamics and was well toleratedat a dose of 125 mg twice daily.15 The objectives of the currentBosentan Randomized Trial of Endothelin Antagonist Therapy (BREATHE-1)were to investigate the effect of bosentan on exercise capacityin a larger number of patients with pulmonary arterial hypertension(including patients in WHO functional class IV [defined as havingsymptoms at rest]) and to compare two doses (125 and 250 mgtwice daily).
Methods
Selection of Patients
We enrolled patients who had symptomatic, severe pulmonary arterialhypertension (WHO functional class16 III or IV) despite treatmentwith anticoagulant drugs, vasodilators, diuretics, cardiac glycosides,or supplemental oxygen. Pulmonary arterial hypertension waseither primary or associated with connective-tissue disease(scleroderma or systemic lupus erythematosus). For ethical reasons,eligible patients in class IV were also required to have a sufficientlystable clinical status to enable them to participate in a placebo-controlledtrial. The inclusion criteria were a base-line six-minute walkingdistance between 150 and 450 m, a resting mean pulmonary-arterypressure greater than 25 mm Hg, a pulmonary-capillary wedgepressure of less than 15 mm Hg, and pulmonary vascular resistancegreater than 240 dyn•sec•cm–5. Patients wereexcluded if they had started or stopped any therapy for pulmonaryarterial hypertension within one month before screening or ifthey had received or had been scheduled to receive long-termtreatment with epoprostenol within three months before screening.To avoid potential drug interactions, patients were also excludedif they were receiving glyburide (glibenclamide) or cyclosporine.
The study was conducted according to the provisions of the HelsinkiDeclaration of 1975, as revised in 1983, and in adherence tolocal guidelines for good clinical practice. The local ethicsreview committees approved the protocol, and written informedconsent was obtained from all patients.
Study Design
The study was designed as a double-blind, randomized, placebo-controlledtrial and was conducted in 27 centers in Europe, North America,Israel, and Australia. All 213 patients were randomly assignedto receive placebo or 62.5 mg of bosentan (Tracleer, Actelion,Allschwil, Switzerland) twice daily for 4 weeks, followed by125 or 250 mg of bosentan twice daily for 12 weeks. All patientsthen continued to take study medication in a double-blind manneruntil the end of the study, which was defined as the day thelast enrolled patient completed the assessment at week 16. Allpatients completed period 1 (16 weeks), but only those randomizedwithin the first 2 months participated in period 2, which wasdesigned to collect data on efficacy and safety prospectivelyfor an additional 12 weeks of double-blind treatment. At theend of the study, all patients were eligible to enter an open-labelstudy of bosentan.
Outcome Measures
During period 1, patients were evaluated on an outpatient basisafter 4, 8, 12, and 16 weeks of therapy. The primary efficacymeasure was the change from base line to week 16 in exercisecapacity, indicated by the distance a patient could walk insix minutes.17 The secondary measures of efficacy were the changefrom base line to week 16 in the Borg dyspnea index (a measureof perceived breathlessness on a scale of 0 to 10, with highervalues indicating more severe dyspnea),18 the change from baseline to week 16 in WHO functional class (a modification of theNew York Heart Association class, with higher classes indicatingmore severe disease), and the time from randomization to clinicalworsening (defined as the combined end point of death, lungtransplantation, hospitalization for pulmonary hypertension,lack of clinical improvement or worsening leading to discontinuation,need for epoprostenol therapy, or atrial septostomy). Safetywas assessed on the basis of recorded adverse events, laboratorymeasures, and electrocardiography. If increases in liver aminotransferaselevels were to a value between five and eight times the upperlimit of normal, the dose of the study drug was halved. If increasesin liver aminotransferases were to a value greater than eighttimes the upper limit of normal, treatment was discontinued.During period 2, the patients were evaluated for efficacy andsafety on an outpatient basis at 22 and 28 weeks of therapy.
Statistical Analysis
The data were retained and analyzed by the sponsor, Actelion.All authors had full access to the data and had complete independenceduring the preparation of the manuscript. The null hypothesisof the study was that there would be no difference between patientsreceiving bosentan (both dosage groups combined) and those receivingplacebo in the distributions of the changes from base line inexercise capacity. The required sample of 50 patients in eachof the three groups (the two bosentan groups and the placebogroup) was estimated with the goal of rejecting the null hypothesisif the means of the distributions, with equal standard deviationsof 75 m, differed by at least 45 m according to the Mann–WhitneyU test, with a type I error of 0.05 (two-sided) and 90 percentpower.
Any data missing at the week 16 assessment were derived by usingpredefined replacement rules with the purpose of minimizingbias. For patients who discontinued the study medication becauseof clinical worsening, the values recorded at the time of discontinuationwas used; patients for whom no value was recorded (includingpatients who died) were assigned the worst possible value (0m). For all other patients without a week 16 assessment, thelast six-minute walking distance, score on the Borg dyspneaindex, and WHO functional class were used as week 16 values.
Statistical analyses were completed according to the intentionto treat. The changes in six-minute walking distance, Borg dyspneaindex, and WHO functional class are reported as means and changesfrom base line or as proportions of patients, with the correspondingstandard errors or 95 percent confidence intervals for the combinedbosentan groups and for the placebo group. The change in walkingdistance was to be analyzed in subgroups defined by demographicand prognostic variables. The time from randomization to clinicalworsening was analyzed by the log-rank test, and Kaplan–Meierestimates of the proportions of patients with treatment failureswere calculated. All reported P values are two-sided.
Results
Two hundred thirteen patients were included in the study: 144received bosentan (74 patients were assigned to 125 mg and 70patients to 250 mg), and 69 received placebo. Forty-eight patientscontinued to receive double-blind treatment in period 2. Themean duration of treatment was 129 days in each bosentan groupand 124 days in the placebo group. No instance of breaking ofthe treatment code occurred before the week 16 assessments;only three such breaks occurred during period 2 (up to 28 weeks).
Base-Line Characteristics
The placebo and bosentan groups were well matched with respectto demographic and base-line characteristics (Table 1). In eachgroup, primary pulmonary hypertension was more common than pulmonaryarterial hypertension associated with connective-tissue disease,and more patients were female. As a consequence of the requirementfor a stable base-line status, few patients in class IV wereincluded in the study. All groups were similar in terms of concomitantmedications and duration of the disease before the trial (timesince diagnosis).
Table 1. Demographic and Clinical Characteristics at Base Line in the Placebo and Bosentan Groups.
Exercise Capacity
After 16 weeks of treatment, the distance walked in six minuteswas increased by 36 m in the combined bosentan groups, whereasa deterioration of 8 m occurred in the placebo group, a meandifference of 44 m (95 percent confidence interval, 21 to 67;P<0.001). Although both bosentan doses induced a significanttreatment effect, the placebo-corrected improvement was morepronounced for the dose of 250 mg twice daily than for the doseof 125 mg twice daily (54 m and 35 m, respectively). However,no dose–response relation for efficacy could be ascertained(Figure 1).
Figure 1. Mean (±SE) Change in Six-Minute Walking Distance from Base Line to Week 16 in the Placebo and Bosentan Groups.
P<0.01 for the comparison between the 125-mg dose of bosentan and placebo, and P<0.001 for the comparison between the 250-mg dose and placebo by the Mann–Whitney U test. There was no significant difference between the two bosentan groups (P=0.18 by the Mann–Whitney U test).
Robustness of the Data
The significance of the improvement in exercise capacity withbosentan was confirmed in the per protocol population (i.e.,those for whom there were no violations of the protocol; P<0.001).It was similarly demonstrated when different approaches wereadopted for the substitution of missing data: for example, whenthe missing walking distance for a patient who did not completethe study (because of death or worsening pulmonary arterialhypertension) was replaced by the last measured value carriedforward rather than by the worst possible value (P<0.001).
Subgroup Analyses
The primary efficacy measure was also assessed in differentsubgroups of patients (Figure 2). An improvement in the walk-testperformance of bosentan-treated patients was observed, regardlessof sex, cause of disease, associated congenital heart defect,time from diagnosis, base-line walk-test performance, and base-linehemodynamic measurements. Although a similar treatment effectwas evident in patients with primary pulmonary hypertensionand in those with pulmonary arterial hypertension associatedwith scleroderma, bosentan improved the walking distance frombase line in the patients with primary pulmonary hypertension(by 46 m among 102 patients in the bosentan group, as comparedwith a decline of 5 m among 48 patients in the placebo group),whereas it prevented deterioration in the walking distance amongpatients with scleroderma (an improvement of 3 m among 33 patientsin the bosentan group, as compared with a decline of 40 m among14 patients in the placebo group).
Figure 2. Effect of Treatment on the Six-Minute Walking Distance from Base Line to Week 16 in Various Subgroups.
Bars represent 95 percent confidence intervals. Certain values could not be obtained for some patients. In some cases, very small subgroups of patients have been omitted from the analysis.
Borg Dyspnea Index
The changes in the Borg dyspnea index at week 16 paralleledthe improvements observed in the walking test. Bosentan-treatedpatients had a mean decrease from base line in the Borg dyspneaindex. In the group receiving 125 mg of bosentan twice daily,the index decreased from 3.3±0.3 to 3.2±0.3, amean change of –0.1±0.2. In the group receiving250 mg of bosentan twice daily, the index decreased from 3.8±0.2to 3.3±0.3, a mean change of –0.6±0.2. Inthe group receiving placebo, the index increased from 3.8±0.2to 4.2±0.3, a mean increase of 0.3±0.2. The meantreatment effect was –0.6 in favor of bosentan (95 percentconfidence interval, –1.2 to –0.1). The placebo-correctedimprovement was greater for patients receiving 250 mg (–0.9,P=0.012 by the Mann–Whitney U test) than for those receiving125 mg (–0.4, P=0.42).
WHO Functional Class
At base line, more than 90 percent of the patients were in WHOfunctional class III. By week 16, in the groups receiving 125and 250 mg of bosentan, 38 percent and 34 percent of patients,respectively, had improved to class II (defined as having symptomswith moderate exertion), and 3 percent and 1 percent, respectively,had improved to class I. In contrast, among the patients receivingplacebo, only 28 percent had improved to class II, and nonehad improved to class I (Figure 3). Overall, 42 percent of thebosentan-treated patients and 30 percent of the placebo-treatedpatients were in a better functional class at week 16 than atbase line, resulting in a mean treatment effect of 12 percentin favor of bosentan (95 percent confidence interval, –3to 25 percent).
Figure 3. Change in World Health Organization Functional Class from Base Line to Week 16 in the Placebo and Bosentan Groups.
Higher classes indicate a greater severity of disease.
Clinical Worsening
During the course of the entire study (up to 28 weeks), bosentansignificantly increased the time to clinical worsening, as comparedwith the time in the placebo group (P=0.002) (Figure 4). Inaddition, each component of this end point occurred consistentlymore frequently in the placebo group than in either bosentangroup (Table 2). There was no dose effect at any time, and thedifference from placebo was significant for both doses of bosentan(P=0.01 for 125 mg twice daily, and P=0.01 for 250 mg twicedaily). The difference between treatment groups in the timeto clinical worsening was apparent as early as week 16. Thisdifference was found to be significant when the data from patientswho continued into period 2 were censored at the week 16 assessment(P=0.004).
Figure 4. Kaplan–Meier Estimates of the Proportion of Patients with Clinical Worsening.
Clinical worsening was defined by the combined end point of death, lung transplantation, hospitalization or discontinuation of the study treatment because of worsening pulmonary arterial hypertension, a need for epoprostenol therapy, or atrial septostomy. P<0.05 for the comparison of the bosentan groups with the placebo group at weeks 16 and 28 by the log-rank test. There was no significant difference between the two bosentan groups at weeks 16 and 28 (P=0.87).
Table 3. Most Frequent Adverse Events in the Placebo and Bosentan Groups.
Three patients died during the study (all during period 1):two patients receiving placebo died of aggravated pulmonaryarterial hypertension and one patient receiving 125 mg of bosentantwice daily died of cardiac failure. Three additional patientsreceiving 250 mg of bosentan twice daily died within four weeksafter withdrawal from or completion of the study: two were withdrawnbecause of pneumonia or a worsening condition, and one diedof pulmonary hemorrhage while in the open-label extension study.
Discussion
In a preliminary study of patients with pulmonary arterial hypertension,15bosentan improved exercise capacity and cardiopulmonary hemodynamics.The present multicenter, randomized, placebo-controlled trialestablishes the efficacy of bosentan in improving exercise capacityin a larger number of patients with pulmonary arterial hypertension.A significant improvement was shown in all subgroup analyses.
The six-minute walk test is a reliable tool for the assessmentof exercise capacity in patients with pulmonary arterial hypertension.Furthermore, it is an independent predictor of mortality.19In a study of epoprostenol in patients with primary pulmonaryhypertension, a treatment-related improvement of 47 m was associatedwith improved survival.6 To date, consistent improvement ofexercise capacity in patients with severe pulmonary arterialhypertension has been reported only in open-label studies withcontinuous intravenous epoprostenol,6,7 the only currently approvedtreatment for pulmonary arterial hypertension, and more recentlywith the stable inhaled prostacyclin analogue, iloprost.8 Thisresult indicates the clinical relevance of the magnitude ofthe improvements observed in the present study. In addition,bosentan was found to reduce significantly the risk of clinicalworsening and of the occurrence of all the end points contributingto the definition of clinical worsening.
One limitation of the present study is that patients with pulmonaryarterial hypertension secondary to other diseases, such as portalhypertension or infection with the human immunodeficiency virus,were not included. In addition, the study was not designed toevaluate the long-term effects of bosentan or to demonstrateimproved survival. However, bosentan significantly increasedthe time to clinical worsening and reduced the proportion ofpatients in WHO functional class IV, suggesting that it mayslow the progression of disease. Nevertheless, long-term clinicalexperience is still needed.
In conclusion, the orally administered dual endothelin-receptorantagonist bosentan significantly improves exercise capacityand increases the time to clinical worsening in patients withsevere pulmonary arterial hypertension. Our results confirmthe therapeutic potential of endothelin-receptor blockade inpatients with pulmonary arterial hypertension, either primaryor associated with connective-tissue disease.
Supported by Actelion, Allschwil, Switzerland. All of the authorshave financial relationships with Actelion, the sponsor of thestudy. The relationships differ among the authors, and theyinclude employment, consultancy, membership on scientific advisoryboards, and support for work as investigators.
We are indebted to all the local investigators and staff membersfor their collaboration and commitment, in particular to thefollowing: Australia — C. Corrigan; Belgium — M.Delcroix, E. Vandevelde, and C. Wilmots; France — A. Pélissier;Germany — F. Kleber; Israel — I. Ben-Dov and P.Yaron; Italy — A. Manes and G. Boggian; Mexico —T. Miranda; Poland — A. Torbicki and M. Kurzyna; Spain— M. Gomez-Sanchez and M. Lazaro-Salvador; United Kingdom— S. Haworth, A. Peacock, G. Hamilton, J. Pepke-Zaba,N. Doughty, and H. Wilson; United States — K. Fagan, A.Ford, E. Horn, A. Yoney, R. Channick, K. Kinninger, T. DeMarco,R. Doyle, R. Frantz, V. McLaughlin, S. Murali, R. Oudiz, I.Robbins, R. Schiltz, V. Tapson, A. Bourgeois, B. DeBoisblanc,D. Lau, V. Scott, C. Severson, H. Purl, D. Pearson, M. Panella,L. Rayl, J. Beckman, W. Mason, K. Hange, and A. Krichman. Weare also indebted to Frédéric Bodin, Hilary Quarmby,and Maurizio Rainisio for design of the study, monitoring ofthe clincial and laboratory assessments, performance of thestudy analysis, and assistance with the preparation of the manuscript;and to Sylvie I. Ertel for editorial assistance.
Source Information
From the Division of Pulmonary and Critical Care Medicine, University of California at San Diego, La Jolla (L.J.R.); the University of Colorado Health Sciences Center, Denver (D.B.B.); Babies and Children's Hospital, Columbia Presbyterian Medical Center, New York (R.J.B.); the Università di Bologna, Bologna, Italy (N.G.); the Royal Free Hospital School of Medicine, London (C.M.B.); St. Vincent's Hospital, Darlinghurst, Australia (A.K.); the Instituto Nacional de Cardiología, Mexico City, Mexico (T.P.); Baylor College of Medicine and Methodist Hospital, Houston (A.F.); Actelion, Allschwil, Switzerland (S.R., I.L.); Children's Hospital and Harvard Medical School, Boston (M.L.); and Hôpital Antoine Béclère, Clamart, France (G.S.).
Address reprint requests to Dr. Rubin at the Division of Pulmonary and Critical Care Medicine, University of California at San Diego, 9300 Campus Point Dr., M/C 7372, La Jolla, CA 92037-1330, or at ljrubin{at}ucsd.edu.
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Bosentan for Pulmonary Hypertension
Pereira B. N., Salvi S., Dietrich C. G., Geier A., Lammert F., Rubin L. J., Galiè N., Simonneau G., the Bosentan Randomized Trial of Endothelin Antagonist Therapy Study Investigators
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A correction has been published: N Engl J Med 2002;346(16):1258.
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