An open-label, multicentre pilot study of bosentan in pulmonary arterial hypertension related to congenital heart disease

BACKGROUND:

Bosentan has been shown to be a safe and efficacious treatment for idiopathic pulmonary arterial hypertension (PAH) and PAH associated with connective tissue disease. However, there are limited studies examining the benefits of bosentan in PAH associated with congenital heart disease (CHD).

OBJECTIVE:

The aim of the present pilot study was to explore the safety and efficacy of bosentan in patients with PAH associated with CHD.

PATIENTS AND METHODS:

In the present study, 11 patients with PAH associated with CHD were enrolled to receive bosentan for a minimum of 16 weeks (62.5 mg twice a day for four weeks; thereafter 125 mg twice a day). Safety was assessed by monitoring adverse events, oxygen saturation, systemic blood pressure, pulse, complete blood count and liver function tests. Efficacy was assessed by the World Health Organization functional class, 6 min walk test (6-MWT), modified Borg dyspnea index, echocardiography and the 36-item short form health survey.

RESULTS:

Ten patients completed the 16-week treatment period (one patient withdrew). Bosentan was not associated with a deterioration in resting oxygen saturation (83.0±4.6% at week 16 versus 81.9±6.1% at baseline; P=0.402), or a deterioration in post-6-MWT oxygen saturation (70.1±10.9% at week 16 versus 68.7±15.1% at baseline; P=0.747). Two patients experienced three serious adverse events. The distance walked in 6 min improved significantly by 28 m (P=0.005) at week 16 compared with baseline, and the modified Borg dyspnea index also improved at week 16 compared with baseline (P=0.050). The World Health Organization functional class improved from class III to class II for five of 10 patients (50%). Patients’ self-rated quality of life (36-item short form health survey) demonstrated a non-significant improvement in each of the eight domains. Obtaining reliable echocardiographic measurements was difficult. Most echocardiographic parameters were only measurable on few patients, and none were measured on all patients, questioning the usefulness of echocardiography as a measuring tool for patients with complex CHD.

CONCLUSION:

Bosentan was not associated with worsening of resting oxygen saturation or exercise systemic oxygen saturation, suggesting its potential as a safe treatment option for patients with PAH associated with CHD. Improved 6-MWT and the modified Borg dyspnea index also suggested the possibility of bosentan as an efficacious treatment option for these patients. The results of the present study provide evidence for the need and feasibility of a large randomized, placebo-controlled clinical trial.     

Efficacy and safety of bosentan in adults with simple and complex Eisenmenger's syndrome

Background. Eisenmenger's syndrome (ES) is associated with decreased longevity and reduced functional capacity. Targeted pharmacologic therapies improve functional capacity and survival in these patients. We sought to compare the response of patients with simple vs. complex ES following initiation of bosentan. Methods. ES patients with a history of bosentan use were identified by chart review. Simple ES was defined as ES associated with atrial septal defect, ventricular septal defect, or patent ductus arteriosus. Complex ES consisted of patients with truncus arteriosus and single ventricle congenital heart disease. Six‐minute walking distance (6MWD), maximal oxygen consumption (VO₂ max), brain natriuretic peptide (BNP), and resting oxygen saturation were compared between simple and complex ES patients before and after bosentan treatment. Results. Twenty‐four patients were included (11 simple, 13 complex). Resting oxygen saturation, 6MWD, VO₂ max, and BNP were not significantly different between the two groups prior to bosentan initiation. Ten patients received bosentan monotherapy, and bosentan was used in combination with sildenafil in 13 (five simple, eight complex). One patient received bosentan with iloprost. Mean duration of therapy was 38 ± 14 months in the simple group and 40 ± 8.1 months in the complex group (P= NS). Posttreatment, 6MWD increased from 274 ± 135 m to 326 ± 106 m in simple ES patients (P= .32). 6MWD in patients with complex ES increased from 332 ± 51 m to 364 ± 109 (P= .028). VO₂ max improved from 13.4 ± 3.8 to 17 ± 6 (P= .54) in the simple group, while VO₂ max in the complex group improved from 12.7 ± 2.3 to 15.5 ± 2.2 (P= .17). There was minimal change in BNP or resting oxygen saturation between the groups. Conclusions. Treatment with bosentan is both safe and effective in patients with both simple and complex forms of ES.     

Long-term effect of bosentan therapy on cardiac function and symptomatic benefits in adult patients with Eisenmenger syndrome

BackgroundBosentan improves symptoms in patients with Eisenmenger syndrome (ES). This study evaluated the effect of long-term bosentan therapy on cardiac function and its relation to symptomatic benefits in ES patients.Methods and ResultsTwenty-three consecutive adult ES patients (15 with ventricular septal defect, 6 with atrial septal defect, and 2 with patent ductus arteriosus) underwent standard and tissue Doppler echocardiography before and 24 ± 9 months after bosentan therapy. Echocardiographic measurements included pulmonary arterial systolic pressure (PASP), myocardial performance index (MPI), tricuspid and lateral mitral annular pulsed-wave tissue Doppler systolic (Sa) and early diastolic (Ea) long-axis motions. Patients’ World Health Organization (WHO) functional class, 6-minute walk distance (6MWD), and systemic arterial oxygen saturations (SaO₂) were also recorded. The PASP, WHO functional class, 6MWD, and SaO₂ all improved (118 ± 22 to 111 ± 19 mm Hg, 3.2 ± 0.4 to 2.4 ± 0.5, 286 ± 129 m to 395 ± 120 m, and 84.6 ± 6.5% to 88.8 ± 3.9%, respectively; all P < .01) after therapy. There was also significant improvement in right ventricular (RV) MPI (by 23.9%: 0.46 ± 0.15 to 0.35 ± 0.09) and biventricular long-axis function (tricuspid Sa and Ea: 6.7 ± 1.5 to 8.8 ± 1.7 cm/s and 5.7 ± 1.3 to 7.0 ± 1.2 cm/s, respectively; lateral Sa and Ea: 6.8 ± 1.3 to 8.4 ± 1.5 cm/s and 7.6 ± 2.0 to 8.5 ± 2.1 cm/s, respectively; all P < .05). Posttherapy RV MPI was moderately correlated with PASP and 6MWD.ConclusionsSustained improvement of pulmonary arterial hypertension and RV function in ES patients was evident 2 years after bosentan therapy, and this may provide insights on the symptomatic benefits gained in these patients.     

Bosentan therapy in patients with pulmonary arterial hypertension: the relationship between improvements in 6 minute walk distance and quality of life

Background and objective:   Bosentan, an oral, dual endothelin receptor antagonist, significantly improves functional status, haemodynamic measures and survival in patients with pulmonary arterial hypertension (PAH). However, there are limited data on the effect of bosentan on quality of life (QOL) and its relationship to changes in functional status, as measured by the 6 minute walk distance (6MWD).
Methods:   A retrospective analysis was performed of a large, open-label, multicentre trial (VITAL) of bosentan in patients with PAH. Data for 6MWD were collected at baseline, 3 or 6 months and these results were correlated with QOL measurements collected as part of the assessment of patients enrolled in the trial.
Results:   Sixty-nine patients with PAH (mean age 52 years) who were enrolled in the trial had valid QOL (SF-36) measurements and 6MWD data that could be retrieved from clinical notes. At 3 and 6 months, bosentan therapy improved 6MWD compared with baseline (49.5 m and 47.2 m, respectively, P  < 0.001) as well as QOL domains, with a significant correlation between these two markers on cross-sectional analysis. However, there was a poor relationship when comparing changes in 6MWD with changes in QOL, in response to therapy.
Conclusion:   Bosentan therapy was associated with improvements in QOL and 6MWD for at least 6 months. At all measured time points, there was a close correlation between 6MWD and most QOL domains. QOL is an important parameter and should be considered as part of the standard assessment for any trial investigating therapy in PAH.     

Efficacy and safety of bosentan for pulmonary arterial hypertension in adults with congenital heart disease

The dual endothelin receptor antagonist, bosentan, has been shown to be well tolerated and effective in improving pulmonary arterial hypertension (PAH) symptoms in patients with Eisenmenger syndrome but data from longer-term studies are lacking. The aim of this study was to retrospectively analyze the long-term efficacy and safety of bosentan in adults with PAH secondary to congenital heart disease (PAH-CHD). Prospectively collected data from adult patients with PAH-CHD (with and without Down syndrome) initiated on bosentan from October 2007 through June 2010 were analyzed. Parameters measured before bosentan initiation (62.5 mg 2 times/day for 4 weeks titrated to 125 mg 2 times/day) and at each follow-up (1 month and 3, 6, 9, 12, 18, and 24 months) included exercise capacity (6-minute walk distance [6MWD]), pretest oxygen saturation, liver enzymes, and hemoglobin. Data were analyzed from 39 patients with PAH-CHD (10 with Down syndrome) who had received ≥ 1 dose of bosentan (mean duration of therapy 2.1 ± 1.5 years). A significant (p < 0.0001) average improvement in 6MWD of 54 m over a 2-year period in patients with PAH-CHD without Down syndrome was observed. Men patients had a 6MWD of 33 m greater than women (p < 0.01). In all patients, oxygen saturation, liver enzymes, and hemoglobin levels remained stable. There were no discontinuations from bosentan owing to adverse events. In conclusion, patients with PAH-CHD without Down syndrome gain long-term symptomatic benefits in exercise capacity after bosentan treatment. Men seem to benefit more on bosentan treatment. Bosentan appears to be well tolerated in patients with PAH-CHD with or without Down syndrome.     

Endothelin receptor antagonist therapy in congenital heart disease with shunt-associated pulmonary arterial hypertension: A qualitative systematic review

BACKGROUND:

Congenital heart disease (CHD) with systemic-to-pulmonary shunting is associated with pulmonary arterial hypertension (PAH). There are similar clinical and pathophysiological features between CHD with shunt-associated PAH and idiopathic PAH. Endothelin-receptor antagonists (ERAs) are oral medications that improve pulmonary hemodynamics, symptoms and functional capacity in many PAH patients. However, the role of ERAs in CHD with shunt-associated PAH is unclear.

METHODS:

MEDLINE, EMBASE and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) databases were searched for articles published from 1966 through September 2006, as well as bibliographies of all retrieved papers. All published English-language studies of adult CHD patients with shunt-associated PAH treated with ERAs were reviewed for clinical, functional and hemodynamic outcomes.

RESULTS:

Ten studies of 174 adult CHD subjects with shunt-associated PAH were identified. Other than one placebo-controlled, randomized clinical trial, all studies were open-label, uncontrolled observational trials. Subjects were treated with the ERA bosentan for a mean (± SD) of 9±7 months. Nine studies reported improved World Health Organization (WHO) modification of the New York Heart Association functional class, with 95 of 164 subjects (58%) improving by at least one functional class. The 6 min walk distance improved in all eight studies in which it was assessed. Bosentan was generally well tolerated; 2.3% of subjects withdrew because of elevated liver enzymes. Two patients with WHO functional class IV PAH died during bosentan therapy.

CONCLUSION:

Treatment of CHD patients with shunt-associated PAH with the ERA bosentan is associated with an improvement in functional class and objectively measured exercise capacity. The consistency of the uncontrolled data and the positive results of a single randomized clinical trial suggest a role for ERA therapy in CHD patients with shunt-associated PAH. Caution is suggested when considering bosentan therapy for CHD patients with WHO functional class IV PAH.     

Initial experience with bosentan (Tracleer) as treatment for pulmonary arterial hypertension (PAH) due to congenital heart disease in infants and young children

INTRODUCTION: Bosentan, a dual endothelin-receptor antagonist, has been shown to be an effective treatment option in patients with the idiopathic form of pulmonary arterial hypertension (PAH). We used bosentan as compassionate treatment in infants and young children with congenital heart disease (CHD) who had a) PAH preoperatively representing a contraindication to corrective surgery or b) persisting PAH after corrective surgery causing right heart failure and reduced exercise tolerance. METHODS: Seven children with PAH due to CHD (median age 3.8 years; range 1.5 to 6.4 years) received 3 mg/kg/d bosentan (Tracleer) orally. Clinical, echocardiographic and hemodynamic parameters were measured and laboratory tests performed before treatment and during steady state while on treatment. Routine liver function parameters were monitored monthly. RESULTS: Mean bosentan treatment time was 8.6+/-5 months. During bosentan therapy there were no significant adverse events. The clinical status remained stable or improved in all patients: NYHA class decreased from 2.6+/-0.6 to 1.7+/-0.6 (p<0.05). This was associated with a mean reduction of the right ventricular systolic pressure (RVSP) from 96+/-11 mmHg to 71+/-26 mmHg (p<0.05). CONCLUSIONS: Treatment with bosentan in infants and young children with PAH due to congenital heart disease was tolerated without significant side effects and resulted in stabilization of clinical status. A significant reduction in right ventricular systolic pressure (RVSP) could be demonstrated. These results suggest that the dose regimen used is appropriate and safe for the treatment of infants and children with PAH, resulting in a reduction of pathologically increased pulmonary vascular resistance.     

Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies

Doppler‐defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months. To assess the effect of bosentan in SCD‐PH, two randomized, double‐blind, placebo‐controlled, 16‐week studies were initiated. Safety concerns are particularly relevant in SCD due to comorbid conditions. ASSET‐1 and ‐2 enrolled patients with pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PH), respectively. Haemodynamics and 6‐min walk distance (6MWD) were obtained at baseline and week 16. The studies were terminated due to slow site initiation and patient enrolment (n = 26). Bosentan appeared to be well tolerated. Although sample sizes were limited, in ASSET‐1 at baseline, 6MWD correlated with cardiac output (CO; P = 0·006) with non‐significant inverse correlations between 6MWD and pulmonary vascular resistance (PVR; P = 0·07) and between 6MWD and right atrial pressure (P = 0·08). In ASSET‐2 at baseline, there was a non‐significant correlation between 6MWD and CO (P = 0·06). Due to limited sample sizes, efficacy endpoints were not analysed. However, in both studies, non‐significant increases in CO were observed with bosentan compared to placebo. Similarly, non‐significant decreases in PVR were observed with bosentan. Limited data in SCD‐PH suggest that a low 6MWD predicts a low CO. Standard‐dose bosentan appears to be well tolerated. Further investigation is warranted. Clinicaltrials.gov registration numbers NCT00310830, NCT00313196, NCT00360087.     

Effects of long-term bosentan in children with pulmonary arterial hypertension

OBJECTIVES: This study investigated the long-term outcome of children with pulmonary arterial hypertension (PAH) treated with bosentan therapy, with or without concomitant prostanoid therapy. BACKGROUND: Bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, improves hemodynamics and exercise capacity in adults with PAH; however, limited data are available on its long-term effects in children. METHODS: In this retrospective study, 86 children with PAH (idiopathic, associated with congenital heart or connective tissue disease) started bosentan with or without concomitant intravenous epoprostenol or subcutaneous treprostinil therapy. Hemodynamics, World Health Organization (WHO) functional class, and safety data were collected. RESULTS: At the cutoff date, 68 patients (79%) were still treated with bosentan, 13 (15%) were discontinued, and 5 (6%) had died. Median exposure to bosentan was 14 months. In 90% of the patients (n = 78), WHO functional class improved (46%) or was unchanged (44%) with bosentan treatment. Mean pulmonary artery pressure and pulmonary vascular resistance decreased (64 +/- 3 mm Hg to 57 +/- 3 mm Hg, p = 0.005 and 20 +/- 2 U x m2 to 15 +/- 2 U x m2, p = 0.01, respectively; n = 49). Kaplan-Meier survival estimates at one and two years were 98% and 91%, respectively. The risk for worsening PAH was lower in patients in WHO functional class I/II at bosentan initiation than in patients in WHO class III/IV at bosentan initiation. CONCLUSIONS: These data suggest that bosentan, an oral endothelin ET(A)/ET(B) receptor antagonist, with or without concomitant prostanoid therapy, is safe and efficacious for the treatment of PAH in children.     

Pulmonary Arterial Hypertension Associated with a Congenital Heart Defect: Advanced Medium‐term Medical Treatment Stabilizes Clinical Condition

Objective. Pulmonary arterial hypertension (PAH) associated with congenital heart defect (CHD), and especially Eisenmenger syndrome, is associated with impaired exercise tolerance and reduced quality of life. In this study, we describe medium‐term follow‐up of adult patients with PAH associated with CHD, treated in a single center with different types of advanced medication. Design. The treatment and clinical course of 15 patients (11 female, median age 53, range 28–74 years) with PAH associated with CHD is retrospectively described. Data on patient characteristics, exercise test, right‐heart catheterization, and type of advanced therapy were collected from medical files. Advanced medical therapy consisted of either intravenous prostacyclin, or endothelin receptor antagonists, or phosphodiesterase‐5‐inhibitors. Additional therapy was started in case of persistent clinical deterioration or insufficient improvement with monotherapy. Results. All patients (10 patients with Eisenmenger syndrome, 5 patients with a closed defect and PAH) were exposed to different durations of advanced medication. Median period of treatment was 2.5 (range 0.7–6.3) years. Atrial septal defect, type secundum, was the most frequent underlying diagnosis (n = 10). Most patients (n = 9) received a combination of advanced medical therapy. Six‐minute walk distance (6‐MWD) remained unchanged with an increase of 44 ± 78 m (P = 0.2) and 41 ± 80 m (P = 0.3) compared with baseline after respectively 1 and 2 years of treatment. Younger age was associated with better performance (β = ?7 m per year, P < 0.05), patients younger than 45 years showed a greater improvement in 6‐MWD after 2 years of treatment (P < 0.05). During a mean follow‐up of 23 (range 4–58) months, mean pulmonary arterial pressure (53 ± 24–49 ± 17 mmHg, P = 0.3) and pulmonary vascular resistance (770 ± 1090–650 ± 444 dynes s/cm5, P = 0.7) showed no deterioration. Conclusion. Advanced treatment strategies in patients with PAH associated with CHD are useful. The treatment effect seems to be one of disease stabilization and decreasing the rate of deterioration. Younger age was associated with a greater improvement of 6‐MWD.     

Initial experience with bosentan (Tracleer?) as treatment for pulmonary arterial hypertension (PAH) due to congenital heart disease in infants and young children

Introduction  

Bosentan, a dual endothelin-receptor antagonist, has been shown to be an effective treatment option in patients with the idiopathic form of pulmonary arterial hypertension (PAH). We used bosentan as compassionate treatment in infants and young children with congenital heart disease (CHD) who had a) PAH preoperatively representing a contraindication to corrective surgery or b) persisting PAH after corrective surgery causing right heart failure and reduced exercise tolerance.     

Safety and efficacy of inhaled treprostinil as add-on therapy to bosentan in pulmonary arterial hypertension.

OBJECTIVES: This study evaluated the safety and efficacy of inhaled treprostinil as add-on therapy to oral bosentan in patients with pulmonary arterial hypertension (PAH). BACKGROUND: The addition of a long-acting prostacyclin analogue via the inhaled route might be a safe and effective strategy to optimize therapy in PAH patients on bosentan. METHODS: Twelve patients with symptomatic PAH despite bosentan received either 30 microg of inhaled treprostinil 4 times daily (n = 6) or 45 microg 4 times daily (n = 6), via an ultrasonic nebulizer. Six-min walk distance (6MWD), functional class, and hemodynamics were assessed at baseline and 12 weeks. RESULTS: One patient was excluded from analysis due to the subsequent finding of pulmonary capillary hemangiomatosis. In the remaining 11 patients, inhaled treprostinil was safe and well tolerated. Inhaled treprostinil was associated with an increase in 6MWD at 12 weeks (baseline 339 +/- 86, 12 week, 1 h post-inhalation 406 +/- 121 m, 67-m change, p = 0.01). An improvement in 6MWD of 49 m from baseline was noted during the trough period, just before inhalation of treprostinil (p = 0.009). The 6MWD improvement of at least 10% was noted in 1 of 6 patients receiving 30 microg versus 5 of 6 receiving 45 microg. Over 12 weeks, significant decreases were noted in mean pulmonary arterial pressure (-10%) and in pulmonary vascular resistance (-26%). Functional class improved from III to II in 9 of 11 patients. CONCLUSIONS: This trial suggests that inhaled treprostinil is safe, well tolerated, and associated with significant improvements in exercise capacity, functional class, and pulmonary hemodynamics in symptomatic patients with PAH on bosentan.     

波生坦治疗特发性肺动脉高压患者的疗效及安全性

目的 观察内皮素受体拮抗剂波生坦治疗中国特发性肺动脉高压患者的有效性、安全性及耐受性.方法 全国多中心Ⅳ期临床试验,共入选79例右心导管等技术确诊的新发特发性肺动脉高压患者,口服波生坦每日2次,每次62.5 mg,治疗4周后增至每日2次,每次125 mg至16周试验结束.分别在基线及治疗16周时记录6分钟步行距离,WHO肺高压功能分级、Borg呼吸困难评分及超声心动图评价资料.结果 波生坦治疗16周后,患者6分钟步行距离从(343.7±93.7)m增至(397.5±104.4)m(P＜0.01),WHO肺高压功能分级显著改善(P＜0.01),Borg呼吸困难评分由3.0±1.5降低至2.5±1.5(P＜0.01),超声心动图估测肺动脉收缩压从(97.8±25.2)mm Hg(1 mm Hg=0.133 kPa)下降至(92.8±29.5)mmHg(P＜0.05).无患者因无法耐受不良反应退出.结论 波生坦能显著改善中国特发性肺动脉高压患者的运动耐量、心功能,且具有良好的安全性和耐受性.

Abstract：

Objective To investigate the efficacy, safety and tolerance of bosentan, a dual endothelin receptor antagonist, in Chinese patients with idiopathic pulmonary arterial hypertension (IPAH).Methods Totally 79 IPAH patients (hemodynamic criteria confirmed by right heart catheterization) were included in this open-label, prospective multicenter study. Patients received 62. 5 mg of bosentan twice daily for the first 4 weeks, and then up-titrated to 125 mg twice daily for another 12 weeks. The primary end point was the change in exercise capacity showed by six-minute walk distance (6MWD) from baseline to 16 weeks. Secondary end points included the change in World Health Organization (WHO) functional class,Borg dyspnoea scale and systolic pulmonary artery pressure measured by echocardiography. Results The 6MWD increased from (343. 7 ± 93.7) meters at baseline to (397.5 ± 104. 4) meters after 16 weeks ( P ＜0. 01 ), WHO functional class and Borg dyspnoea scale were also significantly improved after 16 weeks therapy compared to baseline levels (all P ＜0. 01 ). Furthermore, the systolic pulmonary artery pressure was significantly decreased from (97.8±25.2) mm Hg (1 mm Hg=0. 133 kPa) to (92.8 ±29.5) mm Hg (P ＜0. 05) after 16 weeks bosentan treatment. There was no patient withdrawal from this study for safety consideration. Conclusion Bosentan therapy is well tolerated and can improve the exercise capacity and WHO functional class in Chinese IPAH patients.     

Efficacy of bosentan in a small cohort of adult patients with pulmonary arterial hypertension related to congenital heart disease

OBJECTIVES: This study was designed to assess the tolerability and efficacy of the oral endothelin receptor antagonist bosentan in adult patients with pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). BACKGROUND: Severe PAH in the setting of CHD is a debilitating syndrome for which there are limited treatment options. This is the first long-term study experience in adults reporting on the tolerability and efficacy of therapy with bosentan for this patient population. METHODS: A 12-month single-center experience with 19 women and 5 men with PAH associated with CHD (79% in New York Heart Association [NYHA] class III) was analyzed. Hemodynamic responses, exercise capacity, and Borg dyspnea index were assessed prior to the administration of bosentan, and again at 3, 6, and 12 months after the study began. Clinical assessments were performed monthly for up to 12 months. The change from baseline was tested using the Wilcoxon pairs test. RESULTS: There was significant improvement in hemodynamics from baseline to 12 months (mean [+/- SD] systolic pulmonary arterial pressure, 99 +/- 30 to 87 +/- 28 mm Hg [p 相似文献   

The bosentan patient registry: long‐term survival in pulmonary arterial hypertension

Background/Aims: The Bosentan Patient Registry (BPR) was a prospective, multicentre, Australian registry funded by Actelion Pharmaceuticals. The primary aim of the registry was to collect survival data in patients with pulmonary arterial hypertension (PAH) treated with bosentan. Methods: The BPR was initiated in 15 specialized PAH centres. All patients on or starting bosentan were invited to enrol. Treating physicians notified the registry if patients discontinued bosentan, because of either a change in therapy, transplantation, intervention or death. Survival data were validated against the Australian Institute of Health and Welfare National Death Index. Results: Between 2004 and 2007, a total of 528 patients (mean age 59 ± 17 years) were enrolled representing 69% of patients either previously taking or initiated on bosentan during that time. The BPR population was generally older with more advanced functional deficit than patients enrolled in randomized, placebo‐controlled trials. Aetiology was idiopathic (iPAH) in 58% and connective tissue disease related (scleroderma (SSc)‐PAH) in 42%. For iPAH patients, World Health Organisation functional classes II, III and IV at enrolment was 8.2%, 66.4% and 20.5%, and for the SSc‐PAH cohort, 3.2%, 75.8% and 17.9% respectively. The observed annual mortality was 11.8% in patients with iPAH and 16.6% in patients SSc‐PAH. Conclusion: This large Australian registry provides ‘real life’ information on the characteristics and management of PAH in clinical practice. Treatment with bosentan improved survival outcomes in both iPAH and SSc‐PAH compared with historical controls. Age, disease severity and aetiology were critical factors in determining clinical outcomes.     

Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension

OBJECTIVES: The purpose of this study was to investigate the effects of bosentan (125 or 250 mg twice daily) on echocardiographic and Doppler variables in 85 patients with World Health Organization class III or IV pulmonary arterial hypertension (PAH). BACKGROUND: Bosentan, an orally active dual endothelin-receptor antagonist, improves symptoms, exercise capacity, and hemodynamics in patients with PAH. METHODS: Patients had primary pulmonary hypertension (84%) or PAH associated with connective tissue disease. Of these, 29 patients received placebo and 56 received bosentan (1:2 randomization). Six-minute walk tests and echocardiograms were performed at baseline and after 16 weeks of treatment. RESULTS: Baseline characteristics were similar in the placebo and bosentan groups, and echocardiographic and Doppler findings were consistent with marked abnormalities of right ventricular (RV) and left ventricular (LV) structure and function that were due to PAH. The treatment effect on 6-min walking distance was 37 m in favor of bosentan (p = 0.036). Treatment effects of bosentan compared with placebo on other parameters were as follows: Doppler-derived cardiac index = +0.4 l/min/m(2) (p = 0.007), LV early diastolic filling velocity = +10.5 cm/s (p = 0.003), LV end-diastolic area = +4.2 cm(2) (p = 0.003), LV systolic eccentricity index = -0.12 (p = 0.047), RV end-systolic area = -2.3 cm(2) (p = 0.057), RV:LV diastolic areas ratio = -0.64 (p = 0.007), Doppler RV index = -0.06 (p = 0.03), and percentage of patients with an improvement in pericardial effusion score = 17% (p = 0.05). CONCLUSIONS: Bosentan improves RV systolic function and LV early diastolic filling and leads to a decrease in RV dilation and an increase in LV size in patients with PAH.     

Bosentan use in systemic lupus erythematosus patients with pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) in patients with systemic lupus erythematosus (SLE) is uncommon but is associated with poor survival. This study aimed to examine the long-term effects of bosentan, a dual endothelin-1 receptor antagonist, on symptomatology, haemodynamics and quality of life measures in SLE patients with symptomatic PAH. Four local patients had been followed up prospectively with pre-defined protocol during 12-months of bosentan treatment. Six minute walk distance (6MWD), NYHA functional class, Borg Dyspnoea Index (BDI) and SF-36 were measured at 0, 3, 6, 9 and 12 months. Systolic pulmonary arterial pressure (PAP) was measured by transthoracic echocardiography at zero, six and 12 months. Clinical parameters were analysed, pooling data from other SLE patients reported in the literature (n = 4). Bosentan was found to result in significant improvement in 6MWD compared to baseline [+24.8 m, +26.2 m, +54 m and +62.7 m at three (P = 0.001), six (P = 0.001), nine (P = 0.24) and 12 (P = 0.01) months respectively]. A differential effect was found with greater response in patients with lower exercise capacity. This was accompanied by decrease in NYHA functional class, BDI, transient or sustained drop in systolic PAP and mild improvement in SF-36 domains including mental health, vitality, social function and general health. Significantly deranged liver function was found in one patient.     

Selexipag as Add-on Therapy for Patients with Pulmonary Arterial Hypertension Associated with Congenital Heart Disease: A Single-Center Retrospective Study

Purpose: This study examined the efficacy and safety of selexipag in treating pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD). Materials and Methods: We conducted a retrospective study of patients with CHD-associated PAH, treated with selexipag since December 2017. Thirteen adult patients (mean age, 45.4 years; women, 77%) were treated with selexipag as add-on therapy. Baseline characteristics, World Health Organization functional class, 6-minute walking distance (6MWD) test results, N-terminal pro-B-type natriuretic peptide levels, echocardiographic data, and incidence of side effects were assessed. Results: The majority of patients (12/13, 92.3%) experienced more than one treatment-associated complication; one patient dropped out of the study due to intolerable myalgia. The results of 6MWD test (from 299.2 ± 56.2 m to 363.8 ± 86.5 m, p = 0.039) and tricuspid regurgitation (TR) pressure gradient (from 84.7 ± 20.5 mmHg to 61.6 ± 24.0 mmHg, p = 0.018) improved and remained improved after selexipag treatment in 12 patients. Based on the results of a non-invasive risk assessment, 8 (66.7%) patients showed improvement, 3 (25.0%) showed no interval change, and the status of one patient (8.3%) deteriorated. Moreover, compared to patients treated with a low dosage, patients treated with a medium-to-high dosage showed a greater increase in 6MWD results (88.3 ± 26.4 m vs. 55.3 ± 27.6 m, p = 0.043) and a greater reduction in the TR pressure gradient (−33.7 ± 10.9 mmHg vs. −12.5 ± 12.0 mmHg, p = 0.015). Conclusion: Selexipag is an efficient pulmonary vasodilator as add-on therapy in treating CHD-associated PAH.     

Addition of sildenafil in patients with pulmonary arterial hypertension with inadequate response to bosentan monotherapy

BACKGROUND:

Pulmonary arterial hypertension (PAH) remains a progressive disease despite improvement when using one of three medication classes: prostanoids, endothelin receptor antagonists or phosphodiesterase-5 inhibitors. Combination therapy has been proposed for patients with unsatisfactory response to monotherapy.

OBJECTIVES:

To examine the effect of adding sildenafil to bosentan on 6 min walk distance (6MWD) and New York Heart Association (NYHA) classification in patients with PAH who achieved inadequate improvement with bosentan monotherapy.

METHODS:

Patients with idiopathic PAH or connective tissue disease-associated PAH, and who had either self-reported inadequate improvement in exercise tolerance or a decline in 6MWD after initial improvement, were included in the study (n=10). Data on 6MWD and NYHA class at baseline (before initiation of bosentan), three and six months after baseline, second baseline (before initiation of combination therapy with sildenafil), and three and six months after second baseline were analyzed for any changes.

RESULTS:

Mean time from initiation of bosentan monotherapy to initiation of combination therapy was 558 days (range 150 to 900 days). Six months after initiation of bosentan, 6MWD increased by 57.2 m above the baseline of 314.4 m. Six months after combination therapy, 6MWD was 62.80 m higher than the baseline before initiation of combination therapy of 339 m (P<0.02). The overall increase in 6MWD six months after combination therapy was higher than the first baseline by 87.4 m (P not significant). NYHA functional class did not improve with combination therapy in all patients.

DISCUSSION:

Initiating combination therapy in patients who achieve an inadequate improvement in exercise tolerance with mono-therapy may result in further improvement in exercise tolerance.     

A multinational observational investigation of illness perceptions and quality of life among patients with a Fontan circulation

Objective: First, to compare QOL and illness perceptions between patients with a Fontan circulation and patients with anatomically simple defects (ie, atrial septal defects [ASD] or ventricular septal defects [VSD]). Second, to explore illness perceptions as a mediator of the association between congenital heart disease (CHD) diagnosis and QOL.
Design: Cross-sectional observational study.
Setting: Twenty-four cardiology centers from 15 countries across five continents.
Patients: Four hundred thirty-five adult patients with congenital heart disease (177 Fontan and 258 ASD/VSD) ages 18-83 years.
Outcome Measures: QOL and illness perceptions were assessed by the Satisfaction With Life Scale and the Brief Illness Perceptions Questionnaire, respectively.
Results: Patients with a Fontan circulation reported lower QOL (Wald Z = -3.59, p 5 <.001) and more negative perceptions of their CHD (Wald Z = -7.66, p < .001) compared with patients with ASD/VSD. After controlling for demographics, anxiety, depressive symptoms, and New York Heart Association functional class, path analyses revealed a significant mediation model, αβ = 0.15, p = .002, 95% CI = 0.06-0.25, such that CHD diagnosis was indirectly related to QOL through illness perceptions.
Conclusions: The Fontan sample’s more negative perceptions of CHD were likely a reflection of life with a more complex defect. Illness perceptions appear to account for unique differences in QOL between groups of varying CHD complexity. Psychosocial screening and interventions may be important treatment components for patients with CHD, particularly those with Fontan circulations.