Author + information
- Received May 22, 2008
- Revision received July 23, 2008
- Accepted August 12, 2008
- Published online December 16, 2008.
- Xavier Jaïs, MD⁎,⁎ (, )
- Andrea M. D'Armini, MD†,
- Pavel Jansa, MD‡,
- Adam Torbicki, MD§,
- Marion Delcroix, MD∥,
- Hossein A. Ghofrani, MD¶,
- Marius M. Hoeper, MD#,
- Irene M. Lang, MD⁎⁎,
- Eckhard Mayer, MD††,
- Joanna Pepke-Zaba, MD‡‡,
- Loïc Perchenet, PhD§§,
- Adele Morganti, MSc§§,
- Gérald Simonneau, MD⁎,
- Lewis J. Rubin, MD∥∥,
- BENEFiT Study Group
- ↵⁎Reprint requests and correspondence:
Dr. Xavier Jaïs, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, 157 rue de la Porte de Trivaux, 92140 Clamart, France
Objectives Our goal was to investigate the effect of treatment with the oral dual endothelin receptor antagonist bosentan on the hemodynamics and exercise capacity of patients with chronic thromboembolic pulmonary hypertension (CTEPH).
Background CTEPH is characterized by vascular obstruction and remodeling, leading to increased pulmonary vascular resistance (PVR). Although pulmonary endarterectomy (PEA) is potentially curative, medical therapy is needed in patients with inoperable disease or persistent/recurrent pulmonary hypertension after PEA.
Methods The BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension) study was a double-blind, randomized, placebo-controlled study in CTEPH including patients with either inoperable CTEPH or persistent/recurrent pulmonary hypertension after PEA (>6 months after PEA). Independent coprimary end points were change in PVR as a percentage of baseline and change from baseline in 6-min walk distance after 16 weeks of treatment with bosentan or placebo. Secondary end points included change from baseline in World Health Organization functional class and other hemodynamic parameters.
Results One hundred fifty-seven patients were enrolled and randomized: 80 to placebo, 77 to bosentan. A statistically significant treatment effect (TE) of bosentan over placebo on PVR was demonstrated: −24.1% of baseline (95% confidence interval [CI]: −31.5% to −16.0%; p < 0.0001). Total pulmonary resistance (TE: −193 dyn·s·cm−5; 95% CI: −283 to −104 dyn·s·cm−5; p < 0.0001) and cardiac index (TE: 0.3 l·min−1·m−2; 95% CI: 0.14 to 0.46 l·min−1·m−2; p = 0.0007) improved. Mean TE on 6-min walk distance was +2.2 m (95% CI: −22.5 to 26.8 m; p = 0.5449). Bosentan treatment was well tolerated.
Conclusions This study demonstrated a positive TE of bosentan on hemodynamics in this patient population. No improvement was observed in exercise capacity. Further trials are needed to define the role of medical therapy in patients with CTEPH (Bosentan Effects in Inoperable Forms of Chronic Thromboembolic Pulmonary Hypertension; NCT00313222).
Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition characterized by chronic organized thrombi that obstruct the pulmonary vessels, leading to increased pulmonary vascular resistance (PVR), progressive pulmonary hypertension (PH), and right heart failure (1,2). Although obstruction of pulmonary arteries is recognized as the inciting event, promoting increased PVR and progressive PH, small-vessel arteriopathy is believed to appear in the course of the disease and to contribute to the progression of hemodynamic and symptomatic decline.
The incidence of CTEPH is difficult to assess and may have been underestimated in the past. Recently, in a single-center, prospective, longitudinal study, the cumulative incidence of CTEPH after pulmonary embolism was reported to be 3.8% at 2 years (3).
Pulmonary endarterectomy (PEA) is the treatment of choice, offering immediate hemodynamic benefits and providing a potential cure for many patients (4). However, PEA is not possible for 10% to 50% of patients (inoperable CTEPH), due to either distal pulmonary vascular obstruction that is surgically inaccessible or significant comorbidities thought to be associated with unacceptably high risk (5). Furthermore, in CTEPH patients with disease amenable to surgery, approximately 10% to 15% of patients have residual PH (mean pulmonary arterial pressure [mPAP] >25 mm Hg) (6) after PEA (persistent/recurrent post-operative PH) (7). In these situations, medical treatments may, therefore, be useful. However, there is currently no approved medical therapy for inoperable CTEPH or patients with persistent/recurrent PH post-PEA.
Untreated, CTEPH has a poor prognosis, with over one-half of patients with mPAP >50 mm Hg not surviving beyond 1 year after diagnosis (8). Pulmonary hemodynamics and PVR are believed to be critical, as a significant reduction after surgery is associated with increased survival, and high pre-operative values carry a significant risk of surgical mortality (9,10).
Histopathologic studies of vascular changes in CTEPH have identified vascular lesions similar to those seen in idiopathic pulmonary arterial hypertension (PAH) (11). As in PAH, endothelin (ET)-mediated vascular remodeling has been demonstrated in animal models of CTEPH (12), and increased ET levels and ETB receptor expression have been observed in CTEPH patients (13). For these reasons, the dual ET receptor antagonist, bosentan, which is effective in the treatment of idiopathic PAH as well as PAH associated with other conditions (14–17), appears to be a potential treatment option for inoperable or persistent/recurrent CTEPH. In addition, several uncontrolled trials in CTEPH have suggested that bosentan is effective in improving exercise capacity and hemodynamics (18–20), warranting further study.
The BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension) trial was designed to demonstrate whether bosentan improves PVR and/or exercise capacity (independent coprimary end points) at week 16 in patients with inoperable or persistent/recurrent CTEPH. Secondary objectives were to evaluate the effect of bosentan on time to clinical worsening, World Health Organization (WHO) functional class and hemodynamics, and to evaluate the safety and tolerability of bosentan in this patient population.
In this prospective, multicenter, double-blind, placebo-controlled, parallel-group study, patients were randomized 1:1 to receive bosentan or placebo for 16 weeks. All patients were given an initial dose of 62.5 mg twice a day for 4 weeks, increasing to the target dose of 125 mg twice a day thereafter. Patients weighing <40 kg were maintained at 62.5 mg twice a day throughout the study. This study was conducted in full compliance with the principles of the most recent amendment to the Declaration of Helsinki and with the laws and regulations of the countries in which the research was conducted. All patients gave their informed consent. The protocol and any material provided to the patient were reviewed and approved by the appropriate independent ethics committee or institutional review board before the study was started.
Main inclusion and exclusion criteria
This study included symptomatic PH patients in WHO functional class II, III, or IV who were 18 to 80 years of age with a diagnosis of CTEPH, as demonstrated by ventilation/perfusion lung scanning and pulmonary angiography. Other inclusion criteria included: 1) 6-min walk distance (6MWD) <450 m; 2) mPAP ≥25 mm Hg, pulmonary capillary wedge pressure (PCWP) <15 mm Hg, and PVR at rest ≥300 dyn·s·cm−5; 3) treatment with anticoagulants at an efficacious dose for at least 3 months before randomization; and 4) either CTEPH judged inoperable because of peripheral localization of thrombotic material (according to pulmonary angiography) or persistent/recurrent PH after PEA not amenable to surgery, with no evidence of recurrent thromboembolism. Patients with a distal involvement of pulmonary vessels (chronic thromboembolic lesions only at the segmental and/or subsegmental level) or patients with a high PVR compared with the level of pulmonary obstruction were considered inoperable. Each case was evaluated by a qualified surgeon or an experienced physician, who had to confirm inoperability before the patient could be enrolled. The inoperability of enrolled patients was also assessed retrospectively before unblinding by an Operability Evaluation Committee, which consisted of 2 specialized pulmonologists and 2 PEA surgeons. This committee evaluated the randomized cases; patients unanimously judged to be operable were excluded from the primary analysis.
The main exclusion criteria were: 1) subjects with other forms of PH, including HIV and PH associated with sickle cell disease; and 2) subjects with significant obstructive lung disease (forced expiratory volume in 1 s/forced vital capacity <50% after bronchodilator) or restrictive lung disease (total lung capacity <60% of predicted value). Patients who underwent PEA or suffered from symptomatic pulmonary embolism within 6 months before randomization were also excluded.
Calcium-channel blockers were allowed as concomitant medication if they were started at least 1 month before randomization. Concomitant medication that was forbidden included ximelagatran, sirolimus, fluconazole, glyburide, calcineurin inhibitors, and any targeted treatment specifically for PH.
No large randomized controlled trial had investigated the medical treatment of CTEPH. Therefore, it was unclear which primary end point would be most appropriate. Pulmonary hemodynamics are well-established prognostic factors in CTEPH (8) and are used to guide treatment decisions in clinical practice. However, the 6-min walk test is a reliable tool for the assessment of exercise capacity in PAH patients and is also an independent predictor of mortality (21). Therefore, there was a strong rationale for the use of both PVR and 6MWD as primary end points in a prospective, randomized, controlled trial in CTEPH. Two independent coprimary end points were included for the purpose of assessing efficacy: PVR at rest at week 16 expressed as percent of baseline, and change from baseline to week 16 in 6MWD. The trial was to be considered a positive trial if 1 of these 2 independent coprimary end points was met.
Secondary end points were: change from baseline to week 16 in WHO functional class, cardiac index, total pulmonary resistance, mean right atrial pressure, mPAP, and mixed venous oxygen saturation at rest, and time to clinical worsening (defined as death, lung transplantation, or hospitalization due to worsening of PH). In addition, exploratory end points included: change from baseline to week 16 in N-terminal pro-brain natriuretic peptide (NT-proBNP); Borg dyspnea index assessed immediately after each 6-min walk test, where patients rated their perceived maximal breathlessness during the test on a scale from 0 (nothing at all) to 10 (maximum ever experienced); and quality of life measured using the Short Form 36 (SF-36) health survey questionnaire.
Missing post-baseline values for 6MWD or right heart catheterization were replaced with the last available value carried forward unless death or clinical worsening occurred. In the case of patient death, the value for 6MWD was replaced with “0 m,” and the right heart catheterization parameter was replaced with the “worst value” for that end point. In the case of patients who were unable to undergo right heart catheterization or lacked a value for 6MWD due to clinical worsening, the “worst value” was used. Whenever a missing value for PCWP resulted in a missing PVR value, PVR was calculated using a PCWP value of “0” at both baseline and week 16. For all other parameters, the last available value was carried forward, unless clinical worsening occurred, where the “worst value” was used. The “worst value” for a patient was defined as his or her baseline value corrected for the highest percentage of worsening from baseline observed during the study, or the worst class, index, or grade observed for any patients in the relevant analysis set. Patients were excluded from any efficacy analysis if they had a missing baseline or post-baseline value and no substitution rule applied.
Safety and tolerability assessments included treatment-emergent adverse events occurring during the study period, adverse events leading to discontinuation, and serious adverse events up to 28 days after discontinuation of treatment. Laboratory abnormalities (including aminotransferases and hemoglobin concentrations) were also recorded. Elevations in aminotransferases were recorded as adverse events if they were judged by the investigator to be clinically relevant or if they led to treatment interruption or discontinuation.
The null hypothesis, composed of 2 subhypotheses testing the superiority of bosentan on each of the 2 coprimary end points, was to be rejected if either or both subhypotheses were rejected at their assigned portion of the type-I error (0.01 2-sided for PVR and 0.04 2-sided for 6MWD). The type-I error split was applied to preserve the study-wise type-I error at 0.05 2-sided. The main analysis (for change in PVR or 6MWD) was performed on all randomized excluding operable patients. Treatment comparisons on the 2 coprimary end points were carried out by the Wilcoxon rank sum test. Sample size was determined based on the following power consideration: 94% power to detect a 20% reduction in the geometric mean of percent ratios of week 16/baseline PVR and 80% power to detect a 35 m mean treatment effect on 6MWD. Other efficacy end points were analyzed using the all-randomized set only, with exploratory treatment comparisons performed. For all efficacy end points, treatment effect point estimates with the corresponding 95% 2-sided confidence limits were provided considering the nature of the data: for PVR as (ratio of geometric means of percent ratios of week 16/baseline − 1) × 100, indicating a percent change of bosentan over placebo, for discrete/quantitative variables as difference of means, for binomial variables as relative risk, and for time to clinical worsening as hazard ratio. The proportion of patients improving or worsening in WHO functional class in each treatment group was tested by the Fisher exact test. Safety data were summarized descriptively.
Baseline characteristics and patient disposition
A total of 157 patients were randomized in the study: 80 to the placebo group, 77 to the bosentan group. Demographics and baseline characteristics of the patient population used in the efficacy analyses are shown in Table 1; similar values were also observed for the all-randomized set. Eight patients withdrew prematurely in total: 5 (6.3%) in the placebo group and 3 (3.9%) in the bosentan group (Fig. 1). The Operability Evaluation Committee judged that 11 patients were “operable” and were, therefore, excluded from the analysis (7 in bosentan group, 4 in placebo group). In addition, 9 patients (4 in bosentan group, 5 in placebo group) were excluded from the PVR analysis and 6 patients (3 from each group) from the 6MWD analysis because they had missing baseline or post-baseline values and no substitution rule applied. The mean exposure ± SD (range) was 16.1 ± 2.9 (4.0 to 20.1) weeks in the placebo group and 16.7 ± 2.4 (4.3 to 21.3) weeks in the bosentan group.
Independent coprimary end points
After 16 weeks of treatment, mean PVR decreased from baseline in the bosentan group and increased in the placebo group. This resulted in a statistically significant mean treatment effect of bosentan on PVR of −24.1% (95% confidence interval [CI]: −31.5% to −16.0%; p < 0.0001) (Fig. 2).
Mean change from baseline in 6MWD at week 16 was +2.9 m and +0.8 m for the bosentan and placebo groups, respectively, resulting in a mean treatment effect of +2.2 m (95% CI: −22.5 to 26.8 m; p = 0.5449). A planned subgroup analysis of patients with persistent/recurrent post-PEA PH and those with inoperable CTEPH showed results similar to the main analysis for both independent coprimary end points (Tables 2 and 3).⇓⇓
Secondary end points
Who Functional Class
WHO functional class improved in 14.5% of bosentan-treated patients versus 11.3% in the placebo group at week 16 compared with that seen at baseline (p = 0.6349). Additionally, fewer patients worsened in the bosentan group (2.6% vs. 8.8%; p = 0.1682). However, the treatment effect of bosentan on WHO functional class was not statistically significant (Fig. 3).
Changes in secondary hemodynamic variables are shown in Table 4. Comparison of treatment groups showed that bosentan-treated patients had significant improvement in total pulmonary resistance and cardiac index at week 16.
No statistically significant decrease in the time to clinical worsening was observed with bosentan as compared with that seen with placebo (hazard ratio: 0.63; 95% CI: 0.15 to 2.64). Overall, few clinical worsening events occurred in either treatment group during the 16-week treatment period (5 patients [6.3%] in the placebo group, 3 patients [3.9%] in the bosentan group).
Exploratory end points
At week 16, bosentan-treated patients had a decrease in NT-proBNP concentration, whereas an increase was observed in the placebo group. The mean treatment effect was −622 ng/l in favor of bosentan (p = 0.0034) (Fig. 4).
Borg Dyspnea Index
The Borg dyspnea index at week 16 improved in the bosentan group (−0.4; 95% CI: −0.8 to 0.0) whereas it worsened in the placebo group (+0.2; 95% CI: −0.3 to 0.6). The placebo-corrected treatment effect was −0.6 (p = 0.0386; 95% CI: −1.2 to 0.0).
Quality of Life
The health transition item for the SF-36 questionnaire did not show a difference between the bosentan and placebo groups: the relative risk for worsening was 0.82 (95% CI: 0.38 to 1.76), and the relative risk for improvement was 1.07 (95% CI: 0.74 to 1.53).
Safety and tolerability
The number of patients with at least 1 adverse event was 52 (67.5%) in the bosentan group, compared with 42 (52.5%) in the placebo group. Seven patients (9.1%) in the bosentan group and 10 (12.5%) in the placebo group experienced a serious adverse event, the most common of which was right ventricular failure (bosentan, 2.6%; placebo, 3.8%) and worsening of PH (bosentan 2.6%; placebo 1.3%).
The most common adverse events, reported in ≥5% patients in the bosentan group, were: peripheral edema (bosentan 13.0%; placebo 7.5%), abnormal liver function test (bosentan 7.8%; placebo 1.3%), headache (bosentan 6.5%; placebo 1.3%), right ventricular failure (bosentan 5.2%; placebo 5.0%), nasopharyngitis (bosentan 5.2%; placebo 2.5%), vertigo (bosentan 5.2%; placebo 1.3%), and palpitations (bosentan 5.2%; placebo 0%).
Elevated levels of alanine aminotransferase or aspartate aminotransferase >3× the upper limit of normal were observed in 11 patients (14.5%) in the bosentan group compared with 3 patients (3.8%) in the placebo group. Alanine aminotransferase or aspartate aminotransferase levels >8× the upper limit of normal were reported in 2 patients (2.6%) in the bosentan group and none in the placebo group. Not all of these cases were reported as adverse events.
Two patients in the bosentan group (2.6%) withdrew from the study due to adverse events, compared with 4 in the placebo group (5.0%). One patient from each group discontinued the trial prematurely due to abnormal liver function tests. There were 2 deaths during the study period (including 28-day follow-up), 1 in each study group. Neither death was considered to be related to the study treatment.
The BENEFiT trial is the first multicenter, randomized, placebo-controlled trial in patients with inoperable CTEPH or with persistent/recurrent PH after PEA, a population for whom approved drug therapy is currently lacking. As such, these data represent an important advance in our understanding of CTEPH and the pharmacological management of this disease.
The main finding of this study was a statistically significant improvement in PVR, one of the independent coprimary end points. As pulmonary hemodynamics are believed to be important prognostic factors (8,22), and the assessment of PVR is considered a prerequisite for optimal management of CTEPH in PH expert centers, this finding carries clinical relevance. The reduction of PVR in the bosentan-treated group of over 22% from baseline values is consistent with findings from previous open-label studies of bosentan treatment in CTEPH (18,19,23,24). Similar results were observed when they were adjusted for the stratification factor at randomization according to whether patients had previously undergone surgery. This was also paralleled by a reduction in NT-proBNP levels, which is of interest as NT-proBNP concentrations have been shown to correspond with pulmonary hemodynamics and functional parameters in PAH patients (25) and correlate with the severity of disease in CTEPH patients (26).
However, this hemodynamic improvement did not translate into a favorable effect on exercise capacity. Two other controlled trials have included patients with inoperable CTEPH using 6MWD as the primary end point. The first one was the AIR (Aerosolized Iloprost Randomization) study, which included 57 patients with inoperable CTEPH and 146 PAH patients (27). This study failed to show a significant benefit of inhaled iloprost on exercise capacity in the CTEPH subgroup (28). The second was a 12-week, single-center, placebo-controlled study, which was designed to determine the efficacy of sildenafil in 19 patients with distal CTEPH. This study was underpowered to demonstrate any effect on 6MWD whereas significant improvements in WHO functional status and PVR were observed (29).
The reasons for the discrepancy between the results observed on hemodynamic versus exercise capacity remain unclear. One potential reason is that this particular patient population of CTEPH is older (mean age 63 years) than typical idiopathic PAH patients enrolled in clinical trials. Consequently, in this population, other factors may be involved in the impairment of exercise capacity and could include skeletal muscle deconditioning. Another hypothesis is that the duration of the study was not long enough to demonstrate improvement in exercise capacity as measured by 6MWD.
Data for CTEPH relating to the correlation of exercise capacity with parameters reflecting clinical and hemodynamic severity of the disease are limited. Hemodynamic recovery is immediately obtained after PEA, but recent long-term data suggest that the 6MWD increases gradually and significantly for up to 1 year after surgery (30–32). In fact, the only studies that have shown a positive effect on 6MWD to date have been uncontrolled and open-label and have generally been carried out over a longer period of time than the 16-week study presented here (19,20,33). In addition, because the inclusion/exclusion criteria tend to be less stringent in open-label studies, patients enrolled are frequently less stable than those included in controlled trials and, therefore, may have a greater improvement in exercise capacity under treatment. However, despite these considerations, further studies have to be conducted to assess the long-term clinical effects of medical treatment in patients with CTEPH before the use of these therapies can be recommended in this patient population.
Time to clinical worsening was not significantly different in the 2 groups. However, few clinical worsening events were recorded in both groups. This observation may be explained by the short duration of the study.
Bosentan treatment was well tolerated in this patient population, with a safety profile consistent with results observed in other randomized controlled trials of bosentan in PAH (14,15,34).
Bosentan had a significantly positive effect on hemodynamics, both in patients with inoperable CTEPH and those with persistent/recurrent PH after PEA, and was shown to be well tolerated in this patient population. Nevertheless, the absence of improvement in exercise capacity requires a greater understanding of the disease. Further studies are needed to better determine the role of medical therapy in this population.
The authors would like to thank all of the investigators from the BENEFiT Study Group for their participation in this trial (see Online Appendix) and the 2 PEA specialist members of the Operability Evaluation Committee (Hyong [Nick] Kim, MD, and M. Madani, MD).
For a complete list of investigators, please see the online version of this article.
This study was funded by Actelion Pharmaceuticals. Dr. Jaïs has received consulting fees, speaking fees, and honoraria from Actelion and GlaxoSmithKline. Dr. D'Armini has received consulting fees for service as a Steering Committee member for Actelion Pharmaceuticals. Dr. Jansa has received honoraria from Actelion Pharmaceuticals and fees for consultancies from Actelion, Pfizer, GlaxoSmithKline, and AOP Orphan Pharmaceuticals. Dr. Torbicki has received speaker fees and honoraria for consultations from Actelion, Bayer-Schering, and GlaxoSmithKline. Dr. Delcroix has received consulting fees and research grants from Actelion. Dr. Ghofrani has received honoraria from Actelion, Bayer, Encysive Pharmaceuticals, Ergonex, Pfizer, and GlaxoSmithKline. Dr. Hoeper has received speaker fees and honoraria for consultations from Actelion Pharmaceuticals, Encysive Pharmaceuticals, Pfizer, and Bayer-Schering. Dr. Lang has received honoraria from Actelion, Bayer-Schering, Pfizer, AstraZeneca, GlaxoSmithKline, AOP Orphan Pharmaceuticals, and Encysive Pharmaceuticals, and grant support from Actelion Pharmaceuticals, the EU, and the Austrian government. Dr. Mayer has received speaker fees from Actelion and Bayer. Dr. Pepke-Zaba has received honoraria from Actelion, Encysive Pharmaceuticals, Pfizer, GlaxoSmithKline, and Bayer-Schering, and also holds educational grants funded in part or whole from Actelion, Lung Rx, Pfizer, and Schering. Dr. Simonneau has received honoraria for consultations and/or lecture fees from Pfizer, GlaxoSmithKline, Actelion, Lilly, United Therapeutics, and Bayer, and industry sponsored grants from Pfizer, GlaxoSmithKline, Actelion, Lilly, and United Therapeutics. Dr. Rubin has received consulting fees for service as a Steering Committee member and advisor, and honoraria for lectures from Actelion. Dr. Perchenet and Adele Morganti are employees of Actelion Pharmaceuticals Ltd. Valerie V. McLaughlin, MD, served as Guest Editor for this article.
- Abbreviations and Acronyms
- confidence interval
- chronic thromboembolic pulmonary hypertension
- mean pulmonary arterial pressure
- N-terminal pro-brain natriuretic peptide
- pulmonary arterial hypertension
- pulmonary capillary wedge pressure
- pulmonary endarterectomy
- pulmonary hypertension
- pulmonary vascular resistance
- World Health Organization
- 6-min walk distance
- Received May 22, 2008.
- Revision received July 23, 2008.
- Accepted August 12, 2008.
- American College of Cardiology Foundation
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