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(Chest. 2004;126:808-815.)
© 2004 American College of Chest Physicians

Transition From Epoprostenol and Treprostinil to the Oral Endothelin Receptor Antagonist Bosentan in Patients With Pulmonary Hypertension*

Nizar Suleman, MD and Adaani E. Frost, MD, FCCP

* From Baylor College of Medicine, The Methodist Hospital, Houston, TX.

Correspondence to: Adaani E. Frost, MD, FCCP, SM1236, 6550 Fannin, Houston, TX 77030; e-mail: frost{at}bcm.tmc.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: Prior to the availability of the oral endothelin antagonist bosentan, most patients with pulmonary arterial hypertension (PAH) were treated with continuously infused prostacyclins. Many patients receiving prostacyclins would have received bosentan if it had been available at the time of their diagnosis. Noninvasive criteria (symptoms, World Health Organization [WHO] functional class, 6-min walk test [6MWT] distances, and echocardiograms) are used to govern up-titration of prostacyclins and to assess response to bosentan. The purposes of this study were to see if some patients might be able to transition safely from prostacyclin to bosentan, and whether noninvasive criteria could be used to monitor this transition.

Methods: From January 2002 to July 2003, 23 stable patients with PAH attempted a transition from prostacyclin to bosentan over an 8-week period. 6MWT results, WHO class, and echocardiograms were recorded prior to transition and 1 month after successful transition. The transition was stopped and prostacyclin was resumed or up-titrated if any symptoms of PAH worsened.

Results: Of 23 candidates (19 female and 4 male; age range, 17 to 73 years), 15 patients were transitioned to bosentan. Of these patients, four patients experienced worsening symptoms (range, 7 weeks to 12 months after cessation of prostacyclin) and resumed treatment with prostacyclin. Of the remaining 11 patients, 2 patients had liver function abnormalities 3 months and 10 months after transition to bosentan, respectively; 9 patients remained on bosentan 3 to 16 months after prostacyclin cessation. Patients failing transition and resuming prostacyclin returned to their pretransition functional baseline.

Conclusion: Nine of 23 carefully selected, stable patients with PAH receiving long-term prostacyclin were successfully transitioned to oral bosentan using noninvasive monitoring. No long-term adverse events were associated with failed transition attempts. Further studies need to be carried out to determine which patients are more likely to undergo the transition successfully.

Key Words: bosentan • epoprostenol • hypertension, pulmonary • treprostinil


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Primary pulmonary hypertension (PPH) and pulmonary arterial hypertension (PAH) as a consequence of collagen vascular disease, HIV, and anorexiants are rare diseases associated with significant morbidity and mortality, with historical survival rarely exceeding 5 years.1 Treatment with continuous IV epoprostenol, a prostacyclin, has resulted in a substantial (twofold to threefold) improvement in survival, from a median of 28 months12 to 5 to 6 years for PPH World Health Organization (WHO) class III and IV. Prostacyclin infusions are associated with frequent and bothersome side effects (flushing, jaw pain, diarrhea).23 In addition, they carry the potential for catheter-related infections and sepsis (both local site infections and septicemia).4 Hemodynamic compromise due to abrupt cessation of prostacyclin infusions is potentially life threatening.5 These complications of prostacyclin therapy are associated with patient distress, reduced quality of life, hospitalizations, morbidity, and occasionally mortality. When prostacyclin therapy was introduced for the treatment of PAH, it was for most patients the only therapeutic option. The recent development and release of the endothelin receptor antagonist bosentan has changed the approach to first line of therapy in selected patients with PAH. Most patients with PAH currently receiving prostacyclin therapy would be started on bosentan if they were presenting with that diagnosis today. Therefore, it was believed to be appropriate for use as an alternative to prostacyclin therapy in patients who had improved to WHO class II or III but were still requiring invasive parenteral therapy with prostacyclin to maintain and achieve that status.

The question was how to safely and as noninvasively as possible achieve this transition in patients wishing to proceed in this direction. Patients receiving prostacyclin have their doses adjusted based on examination findings, 6-min walk test (6MWT) results, echocardiograms, WHO functional status, and symptoms. Therefore, we postulated that in stable patients these same noninvasive parameters could be used to assess the safety and efficacy of the transition from prostacyclin to bosentan.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patient Selection
Patients with PAH receiving prostacyclin who wanted to transition from parenteral prostacyclin were assessed for the potential transition to oral bosentan. Patients selected as appropriate for this transition had to demonstrate stability, defined as the need for infrequent (once or less per month) increases in prostaglandin dose, WHO functional class II or III, and with no clinical evidence of heart failure (ie, jugular venous distension, pulsatile liver, lower-extremity edema, etc.). Patients who did not clearly meet these inclusion criteria were excluded from transition. Initial patients considered for transition were limited to those individuals receiving ≤ 50 ng/kg/min of prostacyclin, based on the clinical concern that patients receiving higher doses might be less able to transition successfully. Patients who met the guidelines were provided information on the transition process, risks, and benefits including re-initiation of prostacyclin at higher doses. With greater experience, patients receiving doses of prostacyclin ≥ 50 ng/kg/min were considered. In our clinical experience, treprostinil appears to be approximately one third as potent as epoprostenol, and so patients receiving treprostinil were also considered for transition to oral bosentan based on their medication dosages. There were 50 patients at this institution (excluding those individuals with portopulmonary hypertension) receiving either long-term epoprostenol or treprostinil therapy. All patients considered for transition had been started on prostacyclin for the following indications: WHO III or IV pulmonary hypertension without vasodilator response, or clinically refractory to calcium-channel blocker therapy; pulmonary hypertension, either primary, or secondary to collagen vascular disease, congenital heart disease, or related to HIV; or anorexiants. No patients with thromboembolic pulmonary hypertension were included in this study.

Transition Process
The process of transition was carried out in two 4-week blocks, with a third 4-week observation period prior to removal of permanent central venous catheters.

Initiation:
Bosentan, 62.5 mg q12h, was initiated in the hospital, and the patient was monitored for approximately 18 h (ie, two doses) for potential vasodilator side effects such as hypotension, flushing, nausea, and vomiting. These are side effects of prostacyclin, but we postulated that if bosentan had any immediate vasodilating effects, patients would perceive this as similar to an up-titration in prostacyclin. These symptoms were managed with a prostacyclin dose reduction. Patients required an average reduction in dose of prostacyclin by 2 to 4 ng/kg/min during the initiation phase due to these symptoms. The US Food and Drug Administration (FDA) and manufacturer recommendations were followed for continuing the low dose of bosentan, 62.5 mg q12h, for 1 month before increasing to full therapeutic dose (125 mg q12h).

Up-titration (4 Weeks After Initiation):
After 1 month receiving low-dose bosentan, a 4- to 6-h ambulatory care admission was used to monitor the increase to full-dose bosentan (125 mg q12h). This dosage was continued without modification thereafter, and is the maximum dosage recommended by the manufacturer and the FDA. At this visit, patients were given a schedule for gradual down-titration of prostaglandin infusion, so that they were not receiving prostacyclin 4 weeks later (ie, 8 weeks after bosentan initiation). Simply put, this meant that from week 4 to week 8, the patients were instructed in writing to decrease their prostacyclin usually by 1 to 2 ng/kg on a daily or alternate-day basis such that the prostacyclin was discontinued by week 8. For example, a patient receiving only 10 ng/kg/min of prostacyclin might make only a 2 ng/kg/min decrease in their prostacyclin every 5 to 7 days. A patient receiving 70 ng/kg/min would have to decrease by 2 ng/kg/min every 1 to 2 days. The decision to use an 8-week target for discontinuation of prostaglandin was based on the observed time to maximal effect of bosentan on patients with PAH.6 Patients were advised that if any PAH symptoms developed or increased in frequency or severity they were to abort the prostacyclin down-titration, to resume the dose at which they last felt comfortable, and to notify the physician for further recommendations.

Week 12 Follow-up:
Four weeks after cessation of prostacyclin (in the event that the patients discontinued prostacyclin successfully), the patient was evaluated clinically, and with an echocardiogram and 6MWT. The indwelling catheters for prostacyclin infusion were only removed at this 12-week point if the consensus of these evaluations indicated no deterioration, and if liver function test results were normal.

Noninvasive Monitoring
The 6MWT distance was selected as an end point and surrogate for outcome. This has been found to be a reliable tool for assessment of exercise capacity in patients with PAH, as well as independent predictor of mortality.7 6MWTs were performed using established guidelines.8

Patients underwent comprehensive two-dimensional echocardiography with Doppler evaluation performed using commercially available equipment with two-dimensional and pulsed Doppler capabilities. Hemodynamic parameters including right atrial pressure, pulmonary artery pressure (PAP), and cardiac output were measured according to established guidelines.910

Functional status assessment, 6MWTs, and echocardiography with Doppler were carried out prior to consideration for transition and at 12 weeks. Patient who were remote from the study center and who acquired worsening PAH symptoms during their prostacyclin down-titration, often did not undergo walk tests or echocardiography at 12 weeks as their prostacyclin therapy was increased and the bosentan discontinued before their scheduled re-evaluations.

Serum transaminases and bilirubin were monitored monthly (an FDA requirement for bosentan administration). Standard recommendations for dose reduction or discontinuation were followed. In an asymptomatic patient, if the aspartate transaminase and alanine transaminase levels are more than three times the upper limit of normal or their baseline value, the liver function tests were immediately repeated. If liver function test abnormalities were confirmed, the drug dose was reduced and the liver function tests were repeated in 1 to 2 weeks. If the transaminase levels were more than five times but less than eight times the upper limit of normal, the drug was reduced or stopped, and the values were rechecked immediately and again in 1 to 2 weeks. If the values normalized, consideration was given for drug resumption, but at a lower dosage. For elevations eight or more times the upper limit of normal, the drug was stopped and not resumed. For any elevation of bilirubin greater than two times the upper limit of normal, the drug dosage was reduced and re-evaluated. In the presence of any symptoms of liver dysfunction (eg, anorexia, nausea), the drug dosage was reduced or drug was stopped at lower levels of liver function test abnormality. No patients acquired symptomatic liver function abnormalities or bilirubin elevations.

Office visits were arranged prior to bosentan initiation, at 12 weeks after initiation, and more frequently as indicated. Patients also had periodic telephone follow-up for monitoring of clinical status, and down-titration of prostacyclin.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Twenty-three stable patients with PAH in WHO class II and III receiving continuous prostacyclin infusion attempted transition to oral bosentan. Patient demographics are shown in Table 1 . The patients were predominantly female (19 of 23 patients), and PPH was the predominant diagnosis. Seventeen patients were receiving epoprostenol (10 to 76 ng/kg/min; mean dose, 36 ng/kg/min), and 6 patients were receiving treprostinil (28 to 150 ng/kg/min; mean dose, 79 ng/kg/min).


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  		Table 1. Patient Demographics*

 
Of the original 23 patients, 15 patients successfully completed the transition to bosentan at the end of 12 weeks. Of these 15 patients, however, 4 patients did acquire progressive symptoms of pulmonary hypertension between 7 weeks and 12 months after prostacyclin cessation that necessitated resumption of prostacyclin. These patients were considered late functional/hemodynamic failures. Two of these "late functional failures" occurred within 8 weeks of prostacyclin cessation, and the remaining two failures of transition occurred at 9 months and 12 months following transition, respectively.

The demographics of successful and failed transitions are given in Tables 2, 3 . The group who failed transition to oral bosentan had a higher predominance of male patients (three of four male patients failed transition). While statistical differences have been calculated between the two groups, the small numbers and missing data for some patients make statistical interpretation inappropriate. However, there was a trend for patients who failed transition to have a longer duration of prostacyclin treatment, higher doses of prostacyclin, and higher PAPs as estimated by Doppler echocardiography. There were no other apparent differences between the two groups with regards to age or etiology of pulmonary hypertension.


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  		Table 2. Demographics of Successful Transitions*

 

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  		Table 3. Demographics of Failed Transitions*

 
Two patients who transitioned uneventfully with excellent functional capacity subsequently had to stop the drug due to liver function abnormalities. Liver enzyme elevation occurred 3 months and 10 months after transition (one patient had previously received treprostinil, and one patient had received epoprostenol). These patients were considered successful hemodynamic/functional transitions in evaluating potential predictors of successful transition. Their liver function abnormalities resolved completely and rapidly with cessation of bosentan.

6MWT distance data prior to and after transition was available for 8 of 11 patients who were transitioned successfully to bosentan (Fig 1 , top). Five of eight of these patients demonstrated improvement in their 6MWT distance at the end of the transition period. The mean pretransition and posttransition 6MWT distances in the group completing successful transition were 1,187 feet and 1,215 feet, respectively. Although there was a statistical difference between the pretransition and posttransition walk test distances in this group (p = 0.03, paired t test), the small numbers and some missing data pairs make statistical interpretation inappropriate. The mean pretransition and posttransition 6MWT distances in the transition failures were 1,350 feet and 1,343 feet, respectively. A number of patients who failed their transition to bosentan surprisingly also experienced improvement in their 6MWT distance (Fig 1, bottom). Only one of these patients had received treprostinil; therefore, it is unlikely that relief of site pain would substantially improve the patient’s walking capacity. In the other patients (who were receiving epoprostenol), none had symptoms of leg or foot pain (a side effect of epoprostenol that can sometimes limit walking capacity).



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  		Figure 1. Top: 6MWT distances for eight patients who completed successful transition (data for three patients are missing). Bottom: 6MWT distances for 11 patients who failed transition (data for one patient are missing). PRE = 6MWT distance prior to transition; POST = 6MWT distance at the end of transition (12 weeks).

 
The mean pretransition and posttransition echocardiographic estimates of PAP in the successful transition group were 65.8 mm Hg and 69.9 mm Hg, respectively (p = -0.43, not significant, paired t test). PAP data prior to and after transition were available for 8 of 11 patients who were transitioned successfully to bosentan (Fig 2 , top). One patient demonstrated deterioration in PAP at the end of transition (patient 22), but had no change in the pretransition and posttransition 6MWT distance, WHO class, or symptoms of PAH. There was no statistical difference between the pretransition and posttransition PAP, but the small numbers and some missing data pairs make statistical interpretation inappropriate. Patients who failed transition to oral bosentan demonstrated varying changes in their PAP estimated by echocardiography (Fig 2, bottom).



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  		Figure 2. Top: PAP derived by echocardiogram distances for eight patients who completed successful transition (data for three patients are missing). Bottom: PAP derived by echocardiogram distances for eight patients who failed transition (data for two patients are missing). See Figure 1 legend for expansion of abbreviations.

 
Patients who successfully completed transition to oral bosentan have been followed up from 3 to 14 months (mean, 9.6 months) after completion of transition. WHO functional classes before and after transition for these patients are shown in Table 4 .


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  		Table 4. WHO Functional Class of Patients Before and After Transition

 
Patients failing transition to bosentan continued to receive continuous prostacyclin, sometimes at lower doses; in two instances, a markedly reduced dose of prostacyclin was used in addition to bosentan with improvement in functional capacity relative to pretransition levels. This may be due to the different and presumably synergistic mechanisms of action of prostacyclin and bosentan.1112


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
There is a single, recent article13 that reports successful cessation of epoprostenol in three patients who experienced normalization of their PAPs following years of prostacyclin therapy. This article, from one of the largest pulmonary hypertension centers in the United States, demonstrates the rarity of this occurrence. In contrast, the risk of sudden death with prostacyclin interruption is well recognized. There have been no published studies to date demonstrating safe and effective transition to oral bosentan in patients with persisting significant PAH previously receiving continuous prostacyclin infusion.

This study demonstrates that it is possible to safely and effectively transition carefully selected clinically stable patients with persistent PAH in WHO class II and III receiving continuous prostacyclin infusions to oral bosentan. A significant proportion of patients (15 of 23 patients; 65%) were able to transition to oral bosentan at the end of the 12-week transition period. Late failures and delayed elevation in liver function tests lowered the number of successful transitions to 9 of 23 patients (40%). This remains a substantial treatment and cost benefit to patients otherwise committed by all current criteria to continued therapy with parenteral prostacyclin.

Analysis of this data, limited though it is by small numbers, suggests that only higher doses of prostacyclin and higher PAPs prior to transition appeared to characterize the transition failures. In this small group of patients, no one receiving > 54 ng/kg/min of epoprostenol successfully transitioned to bosentan. Interestingly, patients who failed transition had higher pretransition 6MWT distances compared with those who transitioned successfully, although this difference was not significant. This observation is somewhat inexplicable. Most patients who completed transition to oral bosentan demonstrated improvement or no significant change in their baseline WHO functional class, 6MWT distance, and echocardiographic estimates of PAP.

Abnormal liver function test results occurred in four patients. Bosentan was discontinued in two of these patients after successful hemodynamic transition due to late (ie, after the transition process was completed) elevation in liver function test results. In the other two patients, worsening pulmonary hypertension symptoms (as opposed to elevated liver function test results) were the reason for discontinuation of bosentan.

This study has several limitations. The study design was nonrandomized, nonblinded, and open label. The study population consists of small number of patients, thereby limiting the statistical interpretation of any data. Based on the small numbers of patients in this study as well as missing data for some patients, statistical analysis is not appropriate, and the differences may simply be trends. Preselection bias is obvious and necessary for safety reasons, in that only stable patients who had clearly experienced clinical benefit with prostacyclin were included. The argument could be made that those patients who successfully transitioned off prostacyclin to bosentan perhaps did not even need prostacyclin. This seems unlikely given that all patients still had significant functional limitation (New York Heart Association class II or III), 6MWT limitation (compared to normal subjects), and prominent echocardiographic findings of PAH. The data on outcome in untreated patients with PAH is well established. Therefore, this argument, while philosophically possible, is clinically unlikely. This study was not designed nor should it be interpreted as a comparison of the efficacy of prostacyclin vs an oral endothelin receptor antagonist.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
A significant number of patients with PAH receiving continuous prostacyclin therapy can be effectively and safely transitioned to oral bosentan, thereby reducing the burden of adverse effects experienced by patients due to prostacyclin therapy and the delivery systems. This transition can be successfully and safely achieved using noninvasive monitoring. Patients who were transitioned in this study were carefully selected and had stable disease. Based on this small study, there does not appear to be any significant patient characteristic that predicts success or failure of transition, although there was a trend toward lower doses of prostacyclin therapy and lower PAPs in those who were successfully transitioned. Cautious transition of stable patients with PAH from prostacyclin to bosentan using noninvasive monitoring is both safe and feasible, and is associated with a reasonable likelihood of success.

To offer, potentially, 40% of all patients currently receiving a parenteral prostacyclin a simpler and potentially equally effective drug for some period of time during their limited lifetime is an appropriate and innovative use of this new therapy. Further studies are warranted to assess those patients most likely to achieve both short-term and long-term successful transition from parenteral prostacyclin to oral bosentan therapy.


   Acknowledgements
 
We thank Jan Schneider, RN, and Helena Purl, RN, for their assistance in compiling the data for this study.


   Footnotes
 
Abbreviations: FDA = US Food and Drug Administration; PAH = pulmonary arterial hypertension; PAP = pulmonary artery pressure; PPH = primary pulmonary hypertension; 6MWT = 6-min; WHO = World Health Organization walk test

This work was supported by a research grant from the Frueauff Foundation.

This work was presented in poster form at the American Thoracic Society International Conference 2003, May 16–21, 2003, Seattle, WA, and the presenter was supported by a travel grant from Actelion.

Received for publication October 8, 2003. Accepted for publication April 4, 2004.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. D’Alonzo, GE, Barst, RJ, Ayres, SM, et al (1991) Survival in patients with PPH: results from a national prospective registry. Ann Intern Med 115,343-349[ISI][Medline]
  2. Badesch, DB, Tapson, VF, McGoon, MD, et al Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease: a randomized, controlled trial. Ann Intern Med 2000;132,425-434[Abstract/Free Full Text]
  3. Fishman, AP Epoprostenol (prostacyclin) and pulmonary hypertension. Ann Intern Med 2000;132,500-502[Free Full Text]
  4. Graham, DR, Kelermans, MM, Klemm, LW, et al Infectious complications among patients receiving home intravenous therapy with peripheral, central, or peripherally placed central venous catheters. Am J Med 1991;91,95S-100S[Medline]
  5. Falk, A, Lookstein, RA, Mitty, A Flolan infusion interruption: a lethal complication during venous access. J Vasc Interv Radiol 2001;12,667-668[ISI][Medline]
  6. Rubin, LJ, Badesch, DB, Barst, RJ, et al Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002;346,896-903[Abstract/Free Full Text]
  7. Miyamoto, S, Nagaya, N, Satoh, T, et al 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]
  8. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166,111-117[Free Full Text]
  9. Schiller, NB, Shah, PM, Crawford, M, et al Recommendations for quantitation of the left ventricle by two-dimensional echocardiography: American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2,358-367[Medline]
  10. Quinones, MA, Otto, CM, Stoddard, M, et al Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002;15,167-184[CrossRef][ISI][Medline]
  11. Vane, JR, Botting, RM Pharmacodynamic profile of prostacyclin. Am Cardiol 1995;75,3A-10A
  12. Chen, SJ, Chen, YF, Meng, QC, et al Endothelin-receptor antagonist bosentan prevents and reverses hypoxic pulmonary hypertension in rats. J Appl Physiol 1995;79,2122-2131[Abstract/Free Full Text]
  13. Kim, NH, Channick, RN, Rubin, LJ Successful withdrawal of long-term epoprostenol therapy for pulmonary arterial hypertension. Chest 2003;124,1612-1615[Abstract/Free Full Text]



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