European Heart Journal Advance Access originally published online on January 23, 2006
European Heart Journal 2006 27(5):589-595; doi:10.1093/eurheartj/ehi728
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Long-term outcome with first-line bosentan therapy in idiopathic pulmonary arterial hypertension
Centre des Maladies Vasculaires Pulmonaires (UPRES EA 2705), Service de Pneumologie et Réanimation, AP-HP-Université Paris-Sud, Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92140 Clamart, France
Received 14 July 2005; revised 15 December 2005; accepted 23 December 2005; online publish-ahead-of-print 23 January 2006.
* Corresponding author: Tel: +33 1 45 37 47 79; fax: +33 1 46 30 38 24. E-mail address: olivier.sitbon{at}abc.ap-hop-paris.fr
See page 510 for the editorial comment on this article (doi:10.1093/eurheartj/ehi703)
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Abstract |
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Aims Data on long-term efficacy of bosentan in unselected idiopathic pulmonary arterial hypertension (IPAH) patients are lacking. We aimed to describe the long-term outcome of consecutive IPAH patients treated first-line with bosentan.
Methods and results A retrospective analysis of 103 consecutive New York Heart Association functional class III/IV IPAH patients treated with bosentan at our centre between November 1999 and May 2004 was performed. The 6-minute walk distance (6MWD) and haemodynamics were assessed at baseline and after 4 and 12 months. Mean follow-up was 24±15 months. At 4 months, significant improvements in exercise capacity and haemodynamics were observed and persisted up to 1 year. Overall survival estimates were 90 and 87% and event-free status (survival without transplantation, prostanoid initiation, or hospitalization for right heart failure) estimates were 61 and 44% at 1 and 2 years, respectively. Forty-five (44%) patients required prostanoid therapy during follow-up. The 6MWD and the right atrial pressure at baseline and the 6MWD, the increase in 6MWD, and the decrease in pulmonary resistance after 4 months of treatment were associated with long-term outcomes.
Conclusion In our series of consecutive IPAH patients treated with bosentan, improvements in exercise capacity and haemodynamics were similar to those observed in previous randomized trials. However, on the basis of local criteria, many patients required the addition of prostanoid therapy during follow-up.
Key Words: Hypertension, pulmonary • Endothelin receptor antagonist • Prostacyclin • Follow-up studies • Walk tests
Idiopathic pulmonary arterial hypertension (IPAH) is characterized by a persistent increase in pulmonary vascular resistance which ultimately leads to right heart failure and death.1,2 On conventional therapy, including oral anticoagulants, diuretics, and oxygen, the median survival is less than 3 years.1 In recent years, treatment strategies have evolved including the development of medical therapies that target different pathways involved in the pathogenesis of pulmonary arterial hypertension.3 One of these therapies, bosentan, is an oral, type A and B endothelin receptor antagonist, which was first shown to counteract the vasoconstrictive,4–6 proliferative,4–6 and fibrotic7 effects of endothelin-1 in experimental studies. In two short-term, double-blind, placebo-controlled trials, bosentan significantly improved haemodynamics8 and exercise capacity.8,9 The long-term effects of bosentan on exercise capacity and pulmonary haemodynamics10 and on survival11 during the open-label phase of previous randomized trials8,9 have recently been described. However, patients participating in randomized trials are selected, benefit from very close follow-up, and may not be representative of patients seen by clinicians on an everyday basis. Thus, data on the long-term efficacy of bosentan therapy in a large cohort of unselected IPAH patients are lacking. Furthermore, variables related to long-term outcomes need to be clarified. In this study, we described the long-term effect of first-line bosentan therapy on survival, exercise capacity, and pulmonary haemodynamics in consecutive patients with IPAH seen in our clinic. Demographics, exercise capacity, and haemodynamic characteristics at baseline and during follow-up that are related to patient outcome were also analysed.
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Methods |
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Patients
The 103 consecutive patients with New York Heart Association (NYHA) functional class III or IV IPAH seen in our clinic from November 1999 to May 2004 who were >15 years of age, were treated first-line with bosentan and who did not meet an exclusion criterion were retrospectively evaluated. Patients were excluded if they had pulmonary arterial hypertension related to an associated condition12 or an acute response (defined as a
10 mmHg decrease in mean pulmonary artery pressure to <40 mmHg with a preserved cardiac output) during acute vasoreactivity testing.13 Sixteen patients included in the analysis initially received bosentan as part of a clinical trial.8,9 Their long-term survival has been previously reported after a mean follow-up of 26±8 months.11 For these patients, an additional mean follow-up of 19±7 months is reported in this article. This study complies with the declaration of Helsinki. According to French legislation, the agreement of an ethics committee and informed consent are not required for retrospective collection of data corresponding to current practice. However, the database was anonymized and complied with the restrictive requirements of the ‘Commission Nationale Informatique et Liberté’, the organization dedicated to privacy, information technology, and civil rights in France.
Treatment
All patients received conventional therapy including oral anticoagulants to maintain an international normalized ratio of 2–3 unless contraindicated, diuretics to control peripheral edema, and long-term oxygen therapy if hypoxemia was present. Bosentan was prescribed at the dosage of 62.5 mg twice daily for 4 weeks followed by 125 mg twice daily thereafter. Liver function tests were performed every 2 weeks during the first 2 months and monthly thereafter. Bosentan was stopped or the dosage reduced in cases of elevated liver enzymes in accordance with current recommendations.14
Criteria for addition of prostanoid therapy
At our centre, the need for prostanoid therapy was indicated when the patient was NYHA functional class IV on treatment or persisted in NYHA functional class III after at least 4 months of treatment together with (1) a 6-minute walk distance (6MWD) <250 m, (2) a >10% decrease in 6MWD from the previous value in two tests performed at least 2 weeks apart, or (3) a cardiac index <2.2 L min–1 m–2.
Evaluation
Routine evaluation at baseline included a medical history, an assessment of modified NYHA functional class,3 a physical examination, routine blood tests, and a non-encouraged 6MWD according to the American Thoracic Society recommendations.15 A right heart catheterization was also performed using our standard protocol.16,17 Acute vasodilator testing was performed using nitric oxide inhalation (10 ppm) for 10 min.16 Post-baseline clinical evaluations, including a modified NYHA functional class assessment, a non-encouraged 6-minute walk test, and a right heart catheterization, were routinely performed after 4 and 12 months of bosentan therapy and once a year thereafter.
Statistical analysis
Data were analysed using Statview, version 5.0 (SAS Institute, Cary, NC). All results were expressed as mean±SD. Baseline and post-baseline (after 4 months or 1 year of treatment) values for 6MWD and haemodynamic parameters were compared using two-sided paired Student's t-test. For the subgroup of patients in which baseline, after 4 months and after 1 year, values for 6MWD were available, the comparisons were made using repeated-measures analysis of variance. Only patients on bosentan monotherapy at the time of the evaluation were used for this analysis. A P-value of <0.05 was considered statistically significant.
Analyses of overall survival and event-free status were performed using an intention-to-treat approach. Event-free status was defined as survival without lung transplantation, need of prostanoid therapy, or acute right heart failure requiring hospitalization for intravenous (iv) diuretics and/or dobutamine infusion. Patients who refused or were unable to manage prostanoid therapy when it was indicated were classified as requiring prostanoid therapy. The date of initiation of bosentan therapy was the starting point to determine the follow-up duration. The cut-off date was 1 November 2004. Patients lost to follow-up were censored as of the date of the last bosentan prescription. The Kaplan–Meier method was used to estimate overall survival and event-free status at each time point. For patients with more than one event, only the first event was used in the Kaplan–Meier analysis. Predicted survival was determined using the equation derived from the NIH registry.1 Survival curves were also estimated for patients with a 6MWD above and below the median values at baseline and after 4 months of treatment, and according to the NYHA functional class at the time of the initiation of prostanoid therapy. Survival distributions were compared using the Cox–Mantel log-rank test. Because NYHA functional class at baseline and after 3 months of eposprostenol has been shown to be related to long-term survival in IPAH,2,18 patients' outcome was also described according to their functional class at baseline and after 4 months of bosentan therapy.
Univariate analysis based on the proportional hazards model was used to examine the effect on survival of selected demographic, medical history, exercise capacity, and haemodynamic variables assessed at baseline and after 4 months of bosentan therapy as well as the effect on event-free status of the same variables at baseline. Results were expressed as hazard ratios with 95% confidence intervals.
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Patient characteristics
The patient's clinical characteristics at baseline are presented in Table 1. A history of syncope, right heart failure, and Raynaud's phenomenon were reported in 20, 31, and 9% of patients, respectively.
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Long-term follow-up
The mean duration of follow-up was 24±15 months (median 23 months, range 1–59 months). Two patients did not participate in later evaluations and were lost to follow-up. These patients stopped bosentan therapy after 1 and 11 months, respectively, and were therefore censored at that time.
NYHA functional class and 6-minute walk test
Ninety-nine patients underwent the 4-month evaluation. The remaining four patients either died (n=1), were lost to follow-up (n=2), or did not undergo clinical evaluation (n=1). In these 99 patients, the NYHA functional class improved in 48 patients (48%), remained stable in 42 (42%), and deteriorated in 9 (9%), which resulted in an overall distribution of 40 patients in class II, 51 patients in class III, and eight patients in class IV. The mean 6MWD increased from 322±105 m at baseline to 364±109 m (P<0.001, Figure 1). The 6MWD improved in 74% of patients. The mean Borg dyspnoea score decreased from 3.2±1.8 to 2.6±1.7 (P=0.003).
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At 1 year, six additional patients had died, 13 patients had prostanoid therapy added to bosentan, and one patient did not undergo clinical evaluation. Moreover, at the cut off date, 21 patients on bosentan had not been treated for 1 year. Of the remaining 59 patients evaluated after 1 year on bosentan monotherapy, 41% were classified as NYHA functional class II (n=24) and 59% patients were functional class III (n=33) or IV (n=2). In these 59 patients, the mean 6MWD increased from 349±84 m at baseline to 399±78 m after 4 months of treatment (P<0.001) with no further improvement at 1 year (390±83 m, Figure 1).
Haemodynamics
Seventy-three patients underwent right heart catheterization after 4 months of bosentan monotherapy (Table 2). These patients had a 6MWD similar to that in patients who did not undergo right heart catheterization (n=26) both at baseline (317±94 vs. 335±133 m, P=0.451) and at the time of the 4-month evaluation (361±98 vs. 373±138 m, P=0.637). Overall, pulmonary haemodynamics significantly improved, with a 17% increase in cardiac index, a 19% decrease in total pulmonary resistance, and a slight decrease in mean pulmonary artery pressure. There was no change in systemic haemodynamics.
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After 1 year of bosentan monotherapy, 48 patients underwent right heart catheterization (Table 2). These patients had a 6MWD similar to that in patients who did not undergo right heart catheterization (n=11) both at baseline (344±88 vs. 352±86 m, P=0.800) and at the time of the 1-year evaluation (391±85 vs. 388±77 m, P=0.934). Improvements in cardiac index, total pulmonary resistance, and mean pulmonary artery pressure persisted after 1 year of treatment. The improvements were not associated with a clinically relevant change in heart rate. A decline in mean systemic arterial pressure was observed, but symptomatic hypotension did not occur in any patient.
Survival
Overall survival
The overall survival estimates were 92, 89, and 79% at 1, 2, and 3 years, respectively (Figure 2). The predicted survival at 1, 2, and 3 years, based on the equation derived from the NIH registry,1 was 71, 61, and 51%, respectively. The causes of death were progressive right heart failure (n=10), sudden death (n=1), sepsis related to central catheter infection (n=1), and pneumonia (n=1). Eight of these 13 patients died after prostanoid therapy was added to bosentan and five patients died while on bosentan alone. In the latter group, all had a previous hospitalization for acute right heart failure and two refused the proposed added prostanoid therapy. The results of univariate analysis of the relationship between overall survival and variables measured at baseline and after 4 months of treatment are shown in Tables 3 and 4. The 6MWD (Figure 3A) and right atrial pressure at baseline and the 6MWD (Figure 3B), the increase in 6MWD, and the decrease in total pulmonary resistance after 4 months of treatment were significantly related to overall survival.
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Event-free status
The estimates of event-free status were 63, 45, and 40% at 1, 2, and 3 years, respectively (Figure 2). The first events to occur were the need for added prostanoid therapy (n=34) and acute right heart failure requiring hospitalization for iv diuretics and/or dobutamine infusion (n=17). Among the demographic, clinical, and haemodynamic variables assessed at baseline, only a history of right heart failure and the 6MWD were related to event-free status (Table 3).
Added prostanoid therapy
Added prostanoid therapy was needed by and proposed to 45 patients during follow-up after a mean duration of exposure to bosentan of 12±10 months. The reasons for prostanoid initiation were persistent (n=1) or worsening to NYHA functional class IV (n=17) on treatment, and persistent NYHA functional class III after at least 4 months on bosentan monotherapy with a 6MWD <250 m (n=7), a >10% decrease in 6MWD (n=12), or a cardiac index <2.2 L min–1 m–2 (n=8). Nine of these patients did not have prostanoid therapy initiated because they refused (n=5) or were unable to manipulate inhaled or iv prostanoid medication (n=4). The remaining 36 patients were treated with either iv epoprostenol (n=30) or inhaled iloprost (n=6), most often in combination with continued bosentan (n=34). One patient who received prostanoid therapy died before the next follow-up contact. The remaining 35 patients were evaluated just prior to initiation and after 3 months of prostanoid therapy, and during this period the 6MWD improved from 310±108 to 347±117 m (P=0.031), cardiac index increased from 2.22±0.45 to 2.64±0.63 L min–1 m–2 (P=0.002), and mean pulmonary artery pressure decreased from 60±12 to 56±11 mmHg (P=0.014). In addition, 39% (14 out of 36) of patients improved to NYHA functional class II.
The mean duration of follow-up after the initiation of prostanoid therapy was 15±9 months, and during follow-up, 19% (seven out of 36) of these patients died. The estimated survival rates at 1 and 2 years following prostanoid initiation were 88 and 71%, respectively. Patients belonging to NYHA functional class IV at the time prostanoid therapy was initiated had poorer survival than those in NYHA functional class III (P=0.022, Figure 4). The mean dose of iv epoprostenol at the last follow-up was 20±6 ng/(kg/min).
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Subgroup analyses
NYHA functional class IV at baseline
Twelve patients were NYHA functional IV at baseline. One of these patients died after 34 days of bosentan therapy. After 4 months of treatment, the remaining 11 patients were NYHA functional classes II (n=1), III (n=9), and IV (n=1). During this period, the mean 6MWD improved from 197±93 to 306±84 m (P=0.003). Significant improvements were also seen in cardiac index (2.12±0.41 to 2.54±0.57 L min–1 m–2, P=0.050) and total pulmonary resistance (15.9±5.9 to 12.8±5.6 mmHg L–1 min, P=0.003). The event-free status at 1 year was 37%.
NYHA functional class III after 4 months of treatment
Fifty-one patients were still classified as NYHA functional class III after 4 months of bosentan therapy. The overall survival of these patients at 1 and 2 years was 92 and 89%, respectively, and the event-free status was 51 and 35%, respectively. Twenty-nine of these patients were treated with bosentan monotherapy for at least 1 year. At the 1-year evaluation, three patients were NYHA functional class II, 24 were class III, and two were class IV. Consequently, only 10% (three out of 29) of these patients improved to NYHA functional class II during long-term follow-up.
NYHA functional class II after 4 months of treatment
Forty patients were classified as NYHA functional class II after 4 months of bosentan therapy. In these 40 patients, overall survival was 100% at both 1 and 2 years and the event-free status was 91 and 68%, respectively. Twenty-nine of these patients continued bosentan monotherapy for at least 1 year, and at the 1-year evaluation, 20 patients remained class II and nine (of 29 equal to 31%) had deteriorated to class III. Only one of these patients died (after 28 months of bosentan monotherapy).
Elevated liver enzymes
Bosentan treatment was permanently stopped in three patients because of elevated liver enzymes after 6, 8, and 97 weeks of treatment, respectively. In the first two patients, prostanoid therapy was required 6 and 36 weeks after bosentan discontinuation because of subsequent clinical worsening, whereas the third patient was already on combination therapy with epoprostenol at the time of bosentan discontinuation. Finally, the bosentan dosage was reduced to 62.5 mg twice daily because of elevated liver enzymes in one patient after 8 weeks of bosentan treatment. All patients displayed normalized liver function tests 12 weeks after the bosentan dosage was changed.
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Discussion |
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Two previous short-term placebo-controlled, randomized trials have confirmed the effectiveness of bosentan in the context of IPAH and pulmonary arterial hypertension associated with the scleroderma spectrum of disease.8,9 However, patients recruited in randomized trials may not be representative of patients that clinicians most commonly see on an everyday basis. Furthermore, data on the long-term efficacy of bosentan in IPAH remain fairly limited. This study provides new insights on the long-term clinical and haemodynamic outcome of consecutive patients with IPAH treated with first-line bosentan therapy at a single clinic.
In this study, the mean increase in 6MWD observed after 4 months of treatment was similar to the 70- and 36-m increases observed in previous randomized trials after 12 and 16 weeks, respectively, of bosentan therapy.8,9 Also similar was the 39% (40 out of 103) of our study population that improved to NYHA functional class II during the same period.8,9 Furthermore, improvements in cardiac index, mean pulmonary artery pressure, and total pulmonary resistance were similar to those observed in previous studies.8 As previously described by Sitbon et al.,10 these improvements were sustained in many of our patients. Importantly, however, no further increase in the mean 6MWD was observed after 4 months of bosentan treatment and few patients classified as NYHA functional class III after 4 months subsequently improved to NYHA functional class II during long-term follow-up on bosentan monotherapy.
In our study, the treatment strategy of first-line bosentan therapy with added prostanoid therapy, if necessary, was associated with improved overall survival as compared with the predicted survival based on the equation formulated from the NIH registry, as was previously described by McLaughlin et al.11 It is important to note that these results are not those of bosentan monotherapy, but the results of a treatment approach, with first-line bosentan and prostanoid added if necessary. Contrary to the NIH registry, mean right atrial pressure was the only baseline haemodynamic variable related to survival. The decrease in total pulmonary resistance after 4 months of bosentan therapy was also associated with survival. Both variables have been related to prognosis in epoprostenol-treated patients.2,18
The 6MWD at baseline and after 4 months of treatment and its increase on treatment were also related to survival. The 6MWD has been used as the primary endpoint in most of the recent therapeutic trials.19 The 6MWD achieved before2,20,21 and after 3 months of epoprostenol2 has been shown to correlate with survival in IPAH. This study confirmed the prognostic significance of the increase in the 6MWD on treatment.
The mortality rate in our patients remained low and few patients belonged to NYHA functional class IV at baseline. These factors may explain why NYHA functional class and other variables such as pericardial effusion were not related to prognosis. Although some patients who were NYHA functional class IV at baseline initially benefited from bosentan therapy, most of these patients subsequently required prostanoid therapy. The small number of these patients in the current study precludes any conclusion about the efficacy of bosentan in that setting. Given the high mortality of class IV patients and the more rapid onset of beneficial effect of iv epoprostenol, first-line bosentan should probably be administered to NYHA functional class IV patients only if they refuse or cannot tolerate iv epoprostenol therapy.
Estimates of event-free status were 63, 45, and 40% at 1, 2, and 3 years, respectively, and 44% (45 out of 103) of patients required added prostanoid therapy during follow-up because of persistent unsatisfactory status or clinical worsening after an initial improvement on bosentan. This rate is somewhat higher than reported by McLaughlin et al.11 in which 23% (39 out of 169) of patients treated with first-line bosentan therapy received a prostanoid derivative or an alternative oral therapy during a mean follow-up of 2.1±0.5 years. These differences might be explained by different patient characteristics (baseline 6MWD of 319±105 vs. 345±87 m) and a more aggressive therapeutic approach at our centre. Although most experts agree that patients who deteriorate to NYHA functional class IV should be treated with iv epoprostenol, the best therapeutic approach for patients remaining in NYHA functional class III on first-line therapy is more controversial. In this study, prostanoid therapy was initiated when faced with clearly unsatisfactory results on bosentan monotherapy, such as NYHA functional class IV, poor exercise capacity, deterioration in exercise capacity, or low cardiac index. This treatment strategy is consistent with recent evidence-based guidelines, suggesting that combination therapy might be considered for patients who fail to improve or deteriorate with first-line treatment.19
In patients with NYHA functional class III/IV IPAH, first-line iv epoprostenol therapy has been shown to improve exercise capacity, haemodynamics, and prognosis.2,18,21 Overall survival rates at 1 and 2 years were around 85 and 70%, respectively, with a poorer prognosis for patients in NYHA functional class IV at the time of epoprostenol initiation.2,18 Comparable survival with prostanoid therapy was observed in this study, as were comparable improvements in haemodynamics and exercise capacity, with 39% of NYHA functional class III/IV patients improving to NYHA functional class II after 3 months. Therefore, patients who do not respond to or subsequently deteriorate after an initial response to endothelin receptor antagonists may favourably respond to the initiation of prostanoid therapy. Because most of the clinical improvement observed with bosentan occurred in the first few months of treatment, and long-term prognosis remains poor when iv epoprostenol is initiated in severely ill patients, an alternative therapeutic approach should probably be considered in cases of unsatisfactory results after the first months of bosentan therapy. Subsequent referral for lung transplantation should also be planned if this alternative aggressive therapy remains unsuccessful.
There are several limitations to this observational study. Only patients still on bosentan monotherapy were used to analyse the effect of treatment on exercise capacity and haemodynamics, which certainly has biased the results favourably as patients who needed additional therapy because of poor exercise capacity were excluded from this analysis. Furthermore, two patients were lost to follow-up. Finally, not all patients underwent haemodynamic assessment. This reflects current daily practice, and the similar patient characteristics in terms of exercise capacity at the time of follow-up preclude major bias in the evaluation of haemodynamic improvement.
In conclusion, improvements in exercise capacity and haemodynamics similar to that reported in previous randomized, controlled trials were observed in a large cohort of consecutive and unselected patients treated with first-line bosentan therapy at a single centre. These improvements were sustained in many patients. Furthermore, the treatment strategy of first-line bosentan therapy with added prostanoid therapy, if necessary, improved long-term survival compared with the predicted survival based on the equation formulated from the NIH registry. However, 44% of patients required the addition of prostanoid therapy because of unsatisfactory clinical response on bosentan during follow-up based on local criteria. In addition, simple prognostic factors were documented for IPAH patients treated with first-line bosentan therapy.
Conflict of interest: S.P. has received consultancy fee from Actelion; O.S. has received consultancy and lecture fees from Actelion, Pfizer, Schering AG and GSK; M.H. has received consultancy and lecture fees from Actelion, Pfizer, Schering AG, and United Therapeutics; S.C. hasn't any conflict of interest; X.J. has received lecture fees from Actelion; G.S. has received consultancy and lecture fees from Actelion, Pfizer, Schering AG, Myogen, Encysive and United Therapeutics.
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References |
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TopAbstractMethodsResultsDiscussionReferences |
|---|
- D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, Levy PS, Pietra GG, Reid LM, Reeves JT, Rich S, Vreim CE, Williams GW, Wu M. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115:343–349.[ISI][Medline]
- Sitbon O, Humbert M, Nunes H, Parent F, Garcia G, Herve P, Rainisio M, Simonneau G. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol 2002;40:780–788.
[Abstract/Free Full Text] - Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425–1436.
[Free Full Text] - Eddahibi S, Raffestin B, Clozel M, Levame M, Adnot S. Protection from pulmonary hypertension with an orally active endothelin receptor antagonist in hypoxic rats. Am J Physiol 1995;268:H828–H835.
- Hill NS, Warburton RR, Pietras L, Klinger JR. Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats. J Appl Physiol 1997;83:1209–1215.
[Abstract/Free Full Text] - Rondelet B, Kerbaul F, Motte S, van Beneden R, Remmelink M, Brimioulle S, McEntee K, Wauthy P, Salmon I, Ketelslegers JM, Naeije R. Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension. Circulation 2003;107:1329–1335.
[Abstract/Free Full Text] - Park SH, Saleh D, Giaid A, Michel RP. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997;156:600–608.
[Abstract/Free Full Text] - Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 2001;358:1119–1123.[CrossRef][ISI][Medline]
- Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, Pulido T, Frost A, Roux S, Leconte I, Landzberg M, Simonneau G. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346:896–903.
[Abstract/Free Full Text] - Sitbon O, Badesch DB, Channick RN, Frost A, Robbins IM, Simonneau G, Tapson VF, Rubin LJ. Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: a 1-year follow-up study. Chest 2003;124:247–254.
[Abstract/Free Full Text] - McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N, Rainisio M, Simonneau G, Rubin LJ. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur Respir J 2005;25:244–249.
[Abstract/Free Full Text] - Simonneau G, Galie N, Rubin LJ, Langleben D, Seeger W, Domenighetti G, Gibbs S, Lebrec D, Speich R, Beghetti M, Rich S, Fishman A. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:5S–12S.
[Abstract/Free Full Text] - Sitbon O, Humbert M, Jaïs X, Ioos V, Hamid AM, Provencher S, Garcia G, Parent F, Herve P, Simonneau G. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105–3111.
[Abstract/Free Full Text] - Cohen H, Chahine C, Hui A, Mukherji R. Bosentan therapy for pulmonary arterial hypertension. Am J Health Syst Pharm 2004;61:1107–1119.
[Abstract/Free Full Text] - ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111–117.
[Free Full Text] - Sitbon O, Brenot F, Denjean A, Bergeron A, Parent F, Azarian R, Hervé P, Raffestin B, Simonneau G. Inhaled nitric oxide as a screening vasodilator agent in primary pulmonary hypertension: a dose–response study and comparison with prostacyclin. Am J Respir Crit Care Med 1995;151:384–389.[Abstract]
- Chemla D, Castelain V, Hervé P, Lecarpentier Y, Brimioulle S. Haemodynamic evaluation of pulmonary hypertension. Eur Respir J 2002;20:1314–1331.
[Abstract/Free Full Text] - McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation 2002;106:1477–1482.
[Abstract/Free Full Text] - Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, Olschewski H, Peacock A, Pietra G, Rubin LJ, Simonneau G, Priori SG, Garcia MA, Blanc JJ, Budaj A, Cowie M, Dean V, Deckers J, Burgos EF, Lekakis J, Lindahl B, Mazzotta G, McGregor K, Morais J, Oto A, Smiseth OA, Barbera JA, Gibbs S, Hoeper M, Humbert M, Naeije R, Pepke-Zaba J. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 2004;25:2243–2278.
[Free Full Text] - Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension: comparison with cardiopulmonary exercise testing. Am J Respir Crit Care Med 2000;161:487–492.
[Abstract/Free Full Text] - Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Clayton LM, Jöbsis MM, Blackburn SD, Shortino D, Crow JW, for the Primary Pulmonary Hypertension Study Group. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;334:296–302.
[Abstract/Free Full Text]
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 C. F. Opitz, R. Ewert, W. Kirch, and D. Pittrow Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension: does selectivity matter? Eur. Heart J., August 2, 2008; 29(16): 1936 - 1948. [Abstract] [Full Text] [PDF]
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 K. Boutet, D. Montani, X. Jais, A. Yaici, O. Sitbon, G. Simonneau, and M. Humbert Review: Therapeutic advances in pulmonary arterial hypertension Therapeutic Advances in Respiratory Disease, August 1, 2008; 2(4): 249 - 265. [Abstract] [PDF]
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 C. E. Ventetuolo, R. L. Benza, A. J. Peacock, R. T. Zamanian, D. B. Badesch, and S. M. Kawut Surrogate and Combined End Points in Pulmonary Arterial Hypertension Proceedings of the ATS, July 15, 2008; 5(5): 617 - 622. [Abstract] [Full Text] [PDF]
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 National Pulmonary Hypertension Centres of the UK Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland Heart, March 1, 2008; 94(Suppl_1): i1 - i41. [Full Text] [PDF]
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 National Pulmonary Hypertension Centres of the UK Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland Thorax, March 1, 2008; 63(Suppl_2): ii1 - ii41. [Full Text] [PDF]
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 J. Dupuis and M. M. Hoeper Endothelin receptor antagonists in pulmonary arterial hypertension Eur. Respir. J., February 1, 2008; 31(2): 407 - 415. [Abstract] [Full Text] [PDF]
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 J.G. Coghlan and J. Davar How should we assess right ventricular function in 2008? Eur. Heart J. Suppl., December 1, 2007; 9(suppl_H): H22 - H28. [Abstract] [Full Text] [PDF]
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 R. E Girgis, A. E Frost, N. S Hill, E. M Horn, D. Langleben, V. V McLaughlin, R. J Oudiz, I. M Robbins, J. R Seibold, S. Shapiro, et al. Selective endothelinA receptor antagonism with sitaxsentan for pulmonary arterial hypertension associated with connective tissue disease Ann Rheum Dis, November 1, 2007; 66(11): 1467 - 1472. [Abstract] [Full Text] [PDF]
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 M. Humbert Dual endothelin receptor antagonism: setting standards in PAH Eur. Respir. Rev., August 1, 2007; 16(102): 13 - 18. [Abstract] [Full Text] [PDF]
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 G. Yung Lung Transplantation and Pulmonary Hypertension Seminars in Cardiothoracic and Vascular Anesthesia, June 1, 2007; 11(2): 149 - 156. [Abstract] [PDF]
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M. M. Hoeper Observational trials in pulmonary arterial hypertension: low scientific evidence but high clinical value Eur. Respir. J., March 1, 2007; 29(3): 432 - 434. [Full Text] [PDF]
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S. Provencher Long-term treprostinil in pulmonary arterial hypertension: is the glass half full or half empty? Eur. Respir. J., December 1, 2006; 28(6): 1073 - 1075. [Full Text] [PDF]
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R. J. Barst, N. Galie, R. Naeije, G. Simonneau, R. Jeffs, C. Arneson, and L. J. Rubin Long-term outcome in pulmonary arterial hypertension patients treated with subcutaneous treprostinil Eur. Respir. J., December 1, 2006; 28(6): 1195 - 1203. [Abstract] [Full Text] [PDF]
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M. Gomberg-Maitland Learning to pair therapies and the expanding matrix for pulmonary arterial hypertension: is more better? Eur. Respir. J., October 1, 2006; 28(4): 683 - 686. [Full Text] [PDF]
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M. M. Hoeper, H. Leuchte, M. Halank, H. Wilkens, F. J. Meyer, H. J. Seyfarth, R. Wensel, F. Ripken, H. Bremer, S. Kluge, et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension Eur. Respir. J., October 1, 2006; 28(4): 691 - 694. [Abstract] [Full Text] [PDF]
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 K. Roberts, I. Preston, and N. S. Hill Pulmonary hypertension trials: current end points are flawed, but what are the alternatives? Chest, October 1, 2006; 130(4): 934 - 936. [Full Text] [PDF]
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T. K. Trow Clinical Year in Review II: Occupational Lung Disease, Pulmonary Vascular Disease, Bronchiectasis, and Chronic Obstructive Pulmonary Disease Proceedings of the ATS, September 1, 2006; 3(7): 557 - 560. [Full Text] [PDF]
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R Souza, O Sitbon, F Parent, G Simonneau, and M Humbert Long term imatinib treatment in pulmonary arterial hypertension. Thorax, August 1, 2006; 61(8): 736 - 736. [Full Text] [PDF]
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V. V. McLaughlin 'Raising the bar' for the treatment of pulmonary arterial hypertension Eur. Heart J., March 1, 2006; 27(5): 510 - 511. [Full Text] [PDF]
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