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(Chest. 2005;128:709-713.)
© 2005 American College of Chest Physicians

Bosentan Improves Exercise Tolerance and Tei Index in Patients With Pulmonary Hypertension and Prostanoid Therapy*

Hans-Jürgen Seyfarth, MD; Hans Pankau; Stefan Hammerschmidt, MD; Joachim Schauer, MD; Hubert Wirtz, MD and Jörg Winkler, MD

* From the Department of Pulmonary Medicine, Critical Care and Cardiology, University Leipzig, Leipzig, Germany.

Correspondence to: Hans-Jürgen Seyfarth, MD, Medizinische Universitätsklinik I, Johannisallee 32, D-04103 Leipzig, Germany; e-mail: seyfarth.leipzig{at}freenet.de


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objective: Pulmonary arterial hypertension (PAH) is a progressive disease with a bad prognosis. Prostanoids are well established in the medical treatment of this disease. Treatment of patients with progressive disease despite prostanoids remains a therapeutic challenge. In this study, we examined the effect of adding bosentan, an endothelin antagonist, to existing prostanoid therapy on exercise capacity (6-min walking distance [6MWD]) and right ventricular (RV) function (Tei index) in patients with progressive pulmonary hypertension.

Design: Prospective, nonrandomized, open-label study.

Setting: University hospital.

Patients: Sixteen patients with pulmonary hypertension (PAH, n = 10; pulmonary hypertension due to other cause, n = 6) with progressive disease receiving either beraprost (n = 3), inhaled iloprost (n = 10), or iloprost IV (n = 3).

Interventions: Combination therapy with bosentan (final dosage, 125 mg bid) was initiated following an interval of 3-months minimum of unchanged prostanoid therapy.

Measurements and results: Tei index, 6MWD, and New York Heart Association (NYHA) functional class were assessed prior to the initiation of combination therapy (baseline), at 6 months after initiation of combination therapy, and every 3 months thereafter. Two patients were followed up for 6 months only; all remaining patients reached a mean follow-up period (± SD) of 13.5 ± 5.0 months (range, 9 to 22 months). 6MWD increased by 42.5 ± 66 m at 6 months and 44.6 ± 66 m at the last follow-up (both time points vs baseline, p < 0.001), and Tei index improved by – 0.13 ± 0.08 at 6 months and – 0.13 ± 0.11 at the last follow-up (both time points vs baseline, p < 0.001). All patients reported subjective improvements. Nine of 16 patients exhibited improvement in NYHA functional class at 6 months. No side effects occurred that required dose adjustment or discontinuation of the study medication.

Conclusion: Bosentan administered to patients with progressive pulmonary hypertension receiving prostanoids resulted in an increased exercise capacity and an improved RV function. Bosentan therefore appears to be well suited for combination therapy with prostanoids in selected patients pending results of ongoing randomized trials.

Key Words: beraprost • bosentan • combination • drug therapy • iloprost • pulmonary hypertension


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Pulmonary arterial hypertension (PAH) is a rare, progressive disease with a bad prognosis. Without adequate therapy, the mean survival of patients with primary pulmonary hypertension (PPH) is < 3 years.1 The use of prostanoids has become an effective therapy lately. Continuous IV administration of epoprostenol resulted in improved exercise capacity, quality of life, hemodynamics, and prognosis.234 IV5 as well as inhaled iloprost678 has been shown to evoke similar effects. This has been demonstrated in patients with primary and in patients with various other types of pulmonary hypertension.5910 Oral beraprost11 has also been demonstrated to be effective in a 12-week trial, but failed to cause significant effects at 6 months and 12 months.12 The development of tachyphylaxis seems to be a feature common to all modes of prostanoid therapy.13 Prostanoid dosage is however often limited due to systemic side effects.6

The use of bosentan, an orally administered, dual endothelin receptor antagonist, offers a novel therapeutic strategy. This strategy has been shown to improve exercise capacity in patients with PPH and with PAH associated with systemic sclerosis.1415 Bosentan also led to improvements in right ventricular (RV) function.14 This compound induced hemodynamic effects and exercise capacity improvements that were stable at 12 months of follow-up.16

An experimental study17 as well as a clinical trial18 demonstrated an additive effect of the combination of prostanoid treatment with oral bosentan. Bosentan, 125 mg bid, in combination with beraprost or inhaled iloprost improved 6-min walking distance (6MWD), and parameters of cardiopulmonary exercise testing (oxygen consumption as well as anaerobic threshold) in patients with PPH during a 12-week trial.18

The Tei index is a practical echocardiographic index that combines information on systolic and diastolic RV function. This noninvasive parameter is correlated well with prognosis in patients with chronic pulmonary heart disease due to PPH.19 We hypothesized that adding bosentan may improve Tei index and 6MWD in patients with progressive pulmonary hypertension receiving prostanoid therapy.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patients
Sixteen consecutive patients treated with prostanoids for a minimum of 12 months (Table 1 ) were included in this prospective, nonrandomized, open-label study. Patients were included when progressive pulmonary hypertension was noted despite prostanoid treatment. Progression of disease was defined as follows: (1) a decline of > 15% in 6MWD compared with the individual best value, (2) a decline in cardiac index to < 2 L/min/m2, and/or (3) a failure to increase in cardiac index to > 2 L/min/m2 despite prostanoid treatment. Patients with contraindications for bosentan, especially severe liver dysfunction (Child/Pugh B or C liver cirrhosis), were excluded from the study.


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  		Table 1.. Characteristics of the Included Patients*

 
All patients were receiving long-term oxygen, diuretics, and phenprocoumon; two patients additionally received oral nitrates; and three patients received oral trapidil (a nonspecific phosphodiesterase inhibitor). Prostanoids were administered in the maximum dosage tolerated and were not changed for a minimum period of 3 months before addition of bosentan. All other medications, except diuretics, were also kept constant.

Bosentan was administered starting at an initial dose of 62.5 mg bid. This dose was doubled after 4 weeks unless elevated liver enzymes were observed. Liver enzymes, serum bilirubin, international normalized ratio, and hemoglobin were monitored monthly. The study was approved by the local ethical review board of our institution. Informed consent was obtained from all patients.

Methods
Doppler echocardiography and 6MWD were determined within 3 days before and again at 6 months after initiation of combination therapy. Fourteen patients were followed up for > 6 months. Mean follow-up period was 13.5 ± 5.0 months (range, 9 to 22 months).

6MWD before and after initiation of the combination treatment was determined with supplemental (nasal) oxygen with the flow set to 4 L/min. The walking course was marked on the floor and remained the same throughout the study period.

RV function was characterized by Tei index, the sum of isovolumetric contraction time and isovolumetric relaxation time divided by ejection time.20 The tricuspid inflow velocity was recorded in the four-chamber view using pulsed-wave Doppler echocardiography (Ultramark 7; ATL; Bothell, WA). The sample volume was positioned at the tips of the tricuspid leaflets. Isovolumetric contraction time and isovolumetric relaxation time were obtained from the registration of the tricuspid inflow velocity pattern. The RV tract outflow velocity was recorded from the parasternal short-axis view with the pulsed-wave Doppler sample volume positioned just proximal to the pulmonary valve. Ejection time was measured using the RV outflow velocity pattern. Sweep speed used in all Doppler recordings was 100 mm/s. Five consecutive beats were measured and averaged for each measurement. One of the authors performed the echocardiography. To minimize bias, this investigator did not know the results of the 6MWD test.

Statistics
Data are presented as mean ± SD. The two-tailed Student t test for paired samples was performed for the comparison between baseline values and values of the 6-month and maximum follow-up. Bonferroni correction for multiple testing was applied. The change in 6MWD was correlated with the corresponding Tei index, and the Pearson correlation coefficient was determined.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
6MWD
Figure 1 depicts the results of the 6MWD test. A significant increase in the walking distance was apparent at 6 months after initiation of combination therapy. This improvement was still maintained at the maximum time of follow-up. The increase in the 6MWD was 42.5 ± 66 m at 6 months and 44.6 ± 66 m at the maximum time of follow-up. Six months after initiation of combination therapy the 6MWD was improved in 11 patients (minimum, 16 m; maximum, 196 m), unchanged in 1 patient, and reduced in 4 patients (minimum, 14 m; maximum, 60 m). At the maximum time of follow-up, 6MWD was increased in 10 patients (minimum, 10 m; maximum, 168 m), unchanged in 1 patient, and reduced in 3 patients (minimum, 20 m; maximum, 65 m). The improvement in 6MWD was comparable in both patients with PAH and patients with pulmonary hypertension due to other causes: 6MWD improvement was 42.0 ± 86 m (6 months) and 32.2 ± 67 m (maximum follow-up) in patients with PAH, and 41.0 ± 40 m (6 months) and 66.8 ± 71 m (maximum follow-up) in those with pulmonary hypertension due to other causes.



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  		Figure 1.. 6MWD test. Bottom: 6MWDs of each individual patient immediately prior (pre) to the start of combination therapy (baseline), at 6 months, and at the last follow-up. Each patient is represented by a separate black line. Top: Mean ± SD of all patients. *p < 0.05.

 
RV Function Index
The Tei index at baseline, 6 months, and maximum follow-up is represented in Figure 2 . A significant decrease was noted from 0.46 ± 0.08 at baseline to 0.33 ± 0.06 at 6 months, which was maintained at maximum follow-up (0.33 ± 0.07). Tei index was improved in all patients at the 6-month visit. At the time of maximum follow-up, Tei index was decreased in 12 patients, unchanged in 1 patient, and increased in another patient. The decrease in Tei index was – 0.12 ± 0.08 (6 months) and – 0.11 ± 0.11 (maximum follow-up) in patients with PAH, while it was – 0.14 ± 0.09 (6 months) and – 0.17 ± 0.14 (maximum follow-up) in those with pulmonary hypertension due to other causes. The change in 6MWD at maximum follow-up in all patients exhibited a significant correlation (r = – 0.66, p = 0.006) with the change in Tei index at the same time point (Fig 3 ).



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  		Figure 2.. Tei index. Bottom: Tei indexes of each individual patient immediately prior (pre) to the start of combination therapy (baseline), at 6 months, and at the last follow-up. Each patient is represented by a separate black line. Top: Mean ± SD of all patients. *p < 0.001.

 


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  		Figure 3.. Correlation between changes in Tei index and in 6MWD. The change in 6MWD (last follow-up) is correlated with the corresponding Tei index (Pearson correlation coefficient r = – 0.66; p = 0.006). One patient did not change in Tei index (1), and a another patient experienced an increase in Tei index (2).

 
Table 2 characterizes patients according to New York Heart Association (NYHA) functional class. Nine of 16 patients exhibited improvement in NYHA functional class at 6 months. This improvement was maintained in all patients followed up > 6 months.


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  		Table 2.. Distribution of the Patients With Respect to NYHA Functional Class, Before the Start of the Combination Therapy, at the 6-Month Follow-up, and at the Maximum Follow-up Period

 
Side Effects
Combination therapy was well tolerated. Episodes of arterial hypotension, syncope, or an increase in liver enzymes of more than twofold were not observed. Transient elevated liver enzymes (less than twofold) were observed in one patient receiving 125 mg bid after 6 months of therapy and in one patient receiving 62.5 mg bid. The medication was continued in both cases.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Our findings demonstrate that the addition of the dual endothelin receptor antagonist bosentan to prostanoid therapy significantly improves 6MWD as an indication of increased exercise tolerance and Tei index as an echocardiographic parameter summarizing RV function, in patients with progressive PAH and pulmonary hypertension due to chronic thromboembolic hypertension and due to interstitial lung disease. Several studies141516 have demonstrated that bosentan therapy alone is effective in patients with PPH and PAH associated with scleroderma with NYHA functional class III or IV. We included patients in NYHA functional class II to IV. In addition to these two groups of patients, we included individuals with pulmonary hypertension caused by interstitial lung disease (n = 1), PAH accompanying liver cirrhosis (n = 1), and chronic thromboembolic pulmonary hypertension (n = 5). Few therapeutic options exist to escalate treatment of patients with progression despite prostanoid treatment. Existing options include a switch from oral or inhaled to parenteral prostanoids. This step, however, represents an invasive intervention with known risks such as catheter sepsis or rebound during prolonged interruption. It has been suggested that oral prostanoid therapy may also be switched to inhaled prostanoids because the effects of oral beraprost may be attenuated with increasing treatment time.12 This observation, however, was not available at the time of initialization of our study.

Our suggestion is in accordance with the findings of Hoeper et al,18 who used bosentan in addition to oral or inhaled prostanoids in patients with PPH exclusively and NYHA functional classes III and IV. These authors reported an increase in 6MWD of 58 ± 43 m and an improvement in oxygen consumption as well as anaerobic threshold 3 months after the start of combination therapy in 20 patients with PPH exclusively.18 The improvement was maintained in 11 patients at 6 months.

The results of our study support these observations. The increases in 6MWD of 42.5 ± 66 m at 6 months and of 44.6 ± 66 m at maximum follow-up are comparable to that reported by Hoeper et al.18 However, the duration of follow-up in this study exceeds that of the study of Hoeper et al18 considerably (mean, 13.5 ± 9 months; range, 9 to 22 months). Therefore, the present study suggests that the improvements in exercise tolerance and RV function are maintained for a longer period and may be observed in patients with pulmonary hypertension other than PPH as well.

We used Tei index to evaluate RV performance because it is a practical noninvasive parameter. It is very relevant, as it has been shown to correlate well with prognosis in patients with PPH.19 In addition, 6MWD has also been shown to be correlated with prognosis in PPH.21 Both the improvement in Tei index and in 6MWD observed in this study suggests a prognostic improvement in these patients as a result of combination therapy. One of the authors performed the echocardiography. Although that person did not know the results of the 6MWD test, a bias cannot be completely excluded.

We did not include a control group in this study, and therefore a direct comparison between combination therapy and treatment with prostanoids alone cannot be drawn. However, all patients initially responded to prostanoid therapy. They were included into this study because progression occurred despite increasing prostanoids to the maximally tolerated doses. This dose then had to be unchanged for a minimum of 3 months in order to be able to discriminate changes introduced by the addition of bosentan. It therefore appears likely that the improvement in exercise capacity and RV function is indeed brought about by the addition of bosentan. This study, however, cannot rule out that a replacement of prostanoids by bosentan alone would have been as effective. The small number of patients is another limitation of this study. A study with a larger number of patients should address the direct comparison of combination therapy with bosentan to the replacement of prostanoids by bosentan. Such a randomized study investigating the effect of bosentan addition to IV epoprostenol is ongoing.


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
The present study reports our experience of additional bosentan therapy in patients with progressive pulmonary hypertension despite maximally tolerated prostanoid therapy. The addition of bosentan resulted in a significant improvement of exercise capacity and RV function. This improvement was observed in patients with both PAH and those with pulmonary hypertension of other causes and was maintained for a mean follow-up period of 13.5 months.


   Footnotes
 
Abbreviations: 6MWD = 6-min walking distance; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PPH = primary pulmonary hypertension; RV = right ventricular

Drs. Seyfarth and Pankau contributed equally to this article.

Received for publication January 29, 2004. Accepted for publication January 4, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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