Pulmonary arterial hypertension is a severe disease characterised by a sustained elevation of pulmonary vascular resistance, ultimately leading to right heart failure and death.Reference Galiè, Humbert and Vachiery 1 Disease progression occurs despite the availability of drugs that are specific for the disorder.Reference Benza, Miller, Barst, Badesch, Frost and McGoon 2 Endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin and its analogues have been approved for the treatment of pulmonary arterial hypertension.Reference Channick, Simonneau and Sitbon 3 – Reference Pulido, Adzerikho and Channick 9
Macitentan is an orally active, potent, dual endothelin receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety and characterised by sustained receptor binding and enhanced tissue penetration.Reference Bolli, Boss and Binkert 10 – Reference Keating 13 Compared with the dual endothelin-A/endothelin-B receptor antagonist bosentan and the endothelin-A selective receptor antagonist ambrisentan, macitentan had slower receptor dissociation kinetics.Reference Gatfield, Mueller Grandjean and Sasse 12 The safety profile of macitentan appears to be superior with respect to hepatic safety and oedema than bosentan and ambrisentan, respectively.Reference Pulido, Adzerikho and Channick 9 , Reference Dingemanse, Sidharta and Maddrey 14
Macitentan’s effectiveness was established in the double-blind, randomised, placebo-controlled SERAPHIN study (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve Clinical Outcome) in 2013.Reference Pulido, Adzerikho and Channick 9 The large Phase III study SERAPHIN tested macitentan in more than 700 patients and provided unique long-term outcome data not available for other members of this class.Reference Pulido, Adzerikho and Channick 9 , Reference Dingemanse, Sidharta and Maddrey 14 Macitentan is the only registered treatment for pulmonary arterial hypertension that significantly reduced morbidity and mortality as a combined end point in SERAPHIN study and is approved in the United States of America, the EU, and various other countries for the treatment of pulmonary arterial hypertension.Reference Pulido, Adzerikho and Channick 9 , 15 , 16
Two studies have compared the clinical efficacy and tolerability of switch from bosentan to macitentan only in adult patients with pulmonary arterial hypertension.Reference Blok, van Riel, van Dijk, Mulder and Bouma 17 , Reference Safdar, Thakur and Frost 18 We aimed to evaluate the clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension because of the desirable features of macitentan, such as once-a-day profile and freedom from monthly liver function tests.
Methods
Study design
The study was designed as a single-institution, 24-week prospective observational study in an existing cohort of pulmonary arterial hypertension patients and was conducted in Hacettepe University Hospital, Department of Pediatric Cardiology, Ankara, Turkey. The institutional ethics committee approved the protocol. Written informed consent was obtained from all patients and/or patients’ relatives.
Selection of patients
Patients ⩾12 years of age who had idiopathic or heritable pulmonary arterial hypertension or related to CHD or residual pulmonary arterial hypertension due to repaired congenital systemic-to-pulmonary shunts and on bosentan therapy were included. Confirmation of pulmonary arterial hypertension with right heart catheterisation was required. Patients were required to have a 6-minute walk distance of 300 m or more to be in class II or III according to the World Health Organization functional classification – an adaptation of the NYHA functional classification. Concomitant treatment with oral phosphodiesterase type 5 inhibitors, inhaled prostanoids, digoxin, oral diuretics, and angiotensin-converting enzyme inhibitors was allowed, provided that the patient had been receiving a stable dose for at least 3 months before the study. Patients with Down syndrome and other syndromes were included. Patients in class IV, receiving intravenous prostanoids, with liver or renal impairment, or any other systemic disease were excluded. Macitentan was approved only in patients ⩾12 years of age. Therefore, our study group consisted of patients ⩾12 years of age.
Procedures
Within 1 month after screening, the treatment of patients who were eligible for the study was switched from bosentan to macitentan at a once-daily dose of 10 mg after a 24-hour wash-out period following cessation of bosentan. The maximum plasma concentrations of macitentan are reached in ~8 hours, and macitentan had elimination half-life of ~16 hours. We provided a wash-out period to avoid hepatotoxicity and hypotension, when taking bosentan and macitentan consecutively, by taking a risk that patients on monotherapy did not take any specific treatment for a definite time interval.Reference Keating 13 , Reference Blok, van Riel, van Dijk, Mulder and Bouma 17 , Reference Safdar, Thakur and Frost 18 Patients on combination treatment continued oral phosphodiesterase type 5 inhibitors and inhaled prostanoids. Clinical assessment – including physical examination, 6-minute walk distance test, and functional class – and transthoracic echocardiography were performed by the same cardiologist. Laboratory data, such as haemoglobin, alanine aminotransferase, aspartate aminotransferase, and brain natriuretic peptide levels, were obtained at screening, beginning of the study, and at 12th and 24th weeks. Adverse events such as anaemia, hepatotoxicity, peripheral oedema, or others were recorded throughout the treatment period.
Outcome measures
Outcome measures included change from baseline to week 24, in the 6-minute walk distance, functional class, oxygen saturation at rest and after 6-minute walk distance test, systolic pulmonary artery pressure estimated by echocardiography, and brain natriuretic peptide levels. Safety end points included adverse events and laboratory abnormalities.
Statistical analysis
Change in 6-minute walk distance from baseline to week 12 and week 24 was analysed by repeated measures (within subjects) analysis of variance. Oxygen saturations, at rest and after 6-minute walk distance test, systolic pulmonary arterial pressures estimated by echocardiography, and brain natriuretic peptide levels at 12 and 24 weeks were compared with those at baseline using Friedman’s test. Non-parametric correlations – that is association between disease duration, bosentan duration, number of specific drugs, and 6-minute walk distance at 12th and 24th weeks – were evaluated by Spearman’s rank-order correlation (ρ) coefficient. A p value of less than 0.05 was considered to indicate statistically significant difference. The data analysis was performed by using IBM SPSS Statistics 23 software.
Results
A total of 13 patients – 5 male and 8 female – completed the study. The mean age was 20.3±6.5 years (12–35) and body weight was 54.0±14.5 kg (27–75). Five patients were ⩽18 years of age. Six patients had pulmonary arterial hypertension related to CHD and Eisenmenger syndrome, four patients had residual pulmonary arterial hypertension due to repaired congenital systemic-to-pulmonary shunts, and three patients had idiopathic pulmonary arterial hypertension. A total of 11 patients were in World Health Organization functional class II, and 2 patients were in World Health Organization functional class III. Mean duration of pulmonary arterial hypertension was 10.2±6.7 years (2–22) and patients were on bosentan for 5.8±3.1 years (1–13). Six patients were on monotherapy (bosentan) and seven patients were on combination therapy. Two patients with Down syndrome could not perform 6-minute walk distance test. One patient had Turner syndrome and was able to perform the test. Clinical characteristics of the study patients and 6-minute walk distance test results are shown in Table 1.
Table 1 Clinical characteristics of the study patients and 6-minute walk distance test results.
6-MWD=6-minute walk distance; ACE=angiotension-converting enzyme; AVSD=atrioventricular septal defect; CC-TGA=congenitally corrected transposition of great arteries; DORV=double-outlet right ventricle; PAH=pulmonary arterial hypertension; PDA=patent ductus arteriosus; PDE-5=phosphodiesterase type 5 enzyme; VSD=ventricular septal defect; WHO FC=World Health Organization functional class
Macitentan improved exercise capacity (6-minute walk distance) from baseline (mean: 466±35 m (300–590)), at 12 weeks (mean: 494±78 m (325–590), +28 m) (p<0.05), and at 24 weeks (mean: 507±58 m (325–625), +41 m) (p<0.05) (Figs 1 and 2). We did not observe any statistically significant difference in 6-minute walk distance between 12th and 24th weeks (p<0.05). Functional class of the patients remained unchanged in all patients. Macitentan did not significantly change resting oxygen saturation levels from baseline (median: 88% (60–99)), at 12 weeks (median: 91% (69–99)), and at 24 weeks (median: 93% (60–98)); oxygen saturation levels after 6-minute walk distance test from baseline (median: 87% (55–99)), at 12 weeks (median: 92% (55–99)), and at 24 weeks (median: 89% (60–97)); brain natriuretic peptide levels from baseline (median: 30 pg/ml (10–384)), at 12 weeks (median: 20 pg/ml (10–326)), and at 24 weeks (median: 62 pg/ml (10–362)) (upper limit of normal<100 pg/ml); and systolic pulmonary arterial pressure estimated by echocardiography (p>0.05).
Figure 1 Effect of switch from bosentan to macitentan on 6-minute walk distance over time in patients with pulmonary arterial hypertension.
Figure 2 Comparison of children (⩽18 years) and adult patients (>18 years) with respect to change from baseline to week 24, in the 6-minute walk distance. No statistically significant difference was found between children and adults (p>0.05). Dotted lines show children.
We did not find any significant correlation, in the 6-minute walk distance, between disease duration and change from baseline to week 24 (p>0.05), between bosentan duration and change from baseline to week 24 (p>0.05), and between number of specific drugs and change from baseline to week 24 (p>0.05).
We did not find any statistically significant difference between children and adults with respect to change from baseline to week 24, in the 6-minute walk distance (p>0.05).
None of the patients had anaemia, hepatotoxicity, peripheral oedema, or any other adverse events.
Discussion
According to our preliminary results, in children and young adults with pulmonary arterial hypertension, switch from bosentan to macitentan significantly improved exercise capacity – 6-minute walk distance test – at 24 weeks (+41 m) compared with baseline (p<0.05).
Few studies have been published in literature that compared the clinical efficacy and tolerability of switch from bosentan to macitentan only in adult patients with pulmonary arterial hypertension.Reference Blok, van Riel, van Dijk, Mulder and Bouma 17 , Reference Safdar, Thakur and Frost 18 Blok et al evaluated the effect of a switch from bosentan to macitentan on clinical status after 24 weeks in 40 adult patients with pulmonary arterial hypertension due to CHD (mean age: 45±13 years, 40% male, 40% Down, 75% Eisenmenger)Reference Blok, van Riel, van Dijk, Mulder and Bouma 17 . End points were change in functional class, NT-pro-brain natriuretic peptide levels, tricuspid annular plane systolic excursion, 6-minute walk distance, resting oxygen saturation, ferritin levels, and adverse events. The median treatment duration on bosentan was 7.2 years. Ten (25%) patients were on bosentan–sildenafil combination therapy, 52% of patients were in World Health Organization functional class II, and 48% were in class III.
We evaluated the effect of switch in a younger patient population (13 patients, mean age: 20.3±6.5 years (12–35)). Our study included the youngest patients compared with other studies, and five of our patients were children. We included not only patients with pulmonary arterial hypertension related to CHD as in Blok et al’s study, but also patients with idiopathic/heritable pulmonary arterial hypertension. We were unable to make statistical comparison in 6-minute walk distance according to different pulmonary arterial hypertension aetiology owing to a small number of patients.
Our median treatment duration of bosentan was 5.8±3.1 years (1–13), similar to Blok et al’s study. Although Blok et al reported improvement in functional class (number of patients in functional class III or IV decreased from 48 to 23%), tricuspid annular plane systolic excursion, and NT-pro-brain natriuretic peptide levels, they did not observe any change in 6-minute walk distance, resting oxygen saturations, and ferritin levels. They proposed that the relatively high number of Down syndrome patients (40%) in their cohort might have influenced the overall 6-minute walk distance test results. We observed improvement in 6-minute walk distance. Only two of our patients had Down syndrome and could not perform 6-minute walk distance test. This relatively small number of patients with Down syndrome (15%) compared with Blok et al’s cohort (40%) might explain our results.
In our study, functional class of the patients and brain natriuretic peptide levels remained unchanged. A total of 11 patients were in functional class II and 2 patients were in functional class III; the small number of patients in functional class III might have affected our results. Blok et al also did not report any change in functional class II patients. In addition, in the SERAPHIN study with macitentan, functional class improved from baseline to month 6 in 13% of the patients in the placebo group, as compared with 22% of those in the group that received 10 mg of macitentan.Reference Pulido, Adzerikho and Channick 9
In Blok et al’s study, the number of patients with hospitalisation and syncope did not change, and no serious adverse events were recorded. Liver function tests remained and >1 mmol/L drop in haemoglobin was seen in two patients. One patient died because of sepsis. In our study, none of our patients died or had clinical worsening. The authors concluded that adult patients with pulmonary arterial hypertension due to CHD currently using bosentan might improve from a switch to macitentan under careful follow-up.
In Blok et al’s study, resting oxygen saturation levels did not change significantly and oxygen saturation levels after 6-minute walk distance test were not evaluated.Reference Blok, van Riel, van Dijk, Mulder and Bouma 17 We also did not observe any statistically significant change in both (p>0.05).
Safdar et al evaluated the tolerability of switch to macitentan from bosentan in 24 adult patients with pulmonary arterial hypertension.Reference Safdar, Thakur and Frost 18 The mean age was 58±13 years, duration of the disease was 6.6±4.4 years, and follow-up duration was 5.7±1.5 months. Switch from bosentan to macitentan was well tolerated and safe with no significant change in oedema and liver enzyme levels. Functional class was maintained. Three months following the switch, no significant change was seen in the 6-minute walk distance and brain natriuretic peptide levels. Two patients did not tolerate the switch and had to be returned to bosentan. One patient with portopulmonary hypertension developed elevated alanine aminotransferase and aspartate aminotransferase, and the second patient’s macitentan was stopped because of malaise and tachyarrhythmia.Reference Safdar, Thakur and Frost 18 We observed an improvement in 6-minute walk distance test (+28 m) even 3 months after the switch. In Safdar et al’s study, 30% of the patients had pulmonary arterial hypertension related to connective tissue disease, 25% had idiopathic pulmonary arterial hypertension, and 21% had pulmonary hypertension related to CHD. We propose that macitentan might have a different effect on pulmonary arterial hypertension patients with respect to aetiology, and the effect of switch from bosentan to macitentan in various pulmonary arterial hypertension patients requires further investigation.
Although the most common laboratory abnormality with macitentan was reported as anaemia in the SERAPHIN trial (a haemoglobin level of <8 g/dl occurred in 4.3% of the macitentan group and 0.4% of the placebo group), we did not observe any drop in haemoglobin levels.Reference Pulido, Adzerikho and Channick 9 In the SERAPHIN trial, the incidence of peripheral oedema and hepatotoxicity was similar across macitentan and placebo groups. In addition, the incidence of headache and nasopharyngitis was higher with macitentan than with placebo.Reference Pulido, Adzerikho and Channick 9 In our study, switch from bosentan to macitentan was well tolerated without these adverse events.
Study limitations
The present study was a short-term study with a small number of patients. Our patients had pooling of diagnoses, only included patients with idiopathic/heritable pulmonary arterial hypertension, related to CHD, or residual pulmonary arterial hypertension. Effect of switch from bosentan to macitentan in various pulmonary arterial hypertension patients was not evaluated.
We performed only routine measurements – such as change in 6-minute walk distance, functional class, oxygen saturation at rest and after 6-minute walk distance test, systolic pulmonary arterial pressure estimated by echocardiography, and serum brain natriuretic peptide levels. Haemodynamic data by cardiac catheterisation, before and after the switch, were not available and would have provided more valuable data.
This was a single-arm study in which we did not compare the results with a placebo group. Our study was an unblinded study showing an end point that has a degree of patient effort (change in 6-minute walk distance), which could bias the study.
Conclusions
Our study is the first study that showed that switch from bosentan to macitentan significantly improved exercise capacity in children and young adults with pulmonary arterial hypertension and is well tolerated without any adverse events.
Acknowledgement
None.
Financial Support
This research received no specific grant from any funding agency, commercial or not-for-profit sectors.
Conflicts of Interest
None.
Ethical Standards
The authors assert that all procedures contributing to this work comply with the ethical standards of the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the ethics committee of Hacettepe University. Informed consent was obtained from all individual patients and/or parents.
