Abstract

METHODS

The patient population

Forty children with PAH were treated with bosentan. All were in WHO functional class III and IV except one patient with IPAH who had been treated with intravenous epoprostenol for five years after a cardiac arrest and was now in class II. Twenty patients had IPAH and 20 had secondary PH (​(​tablestables 1–3). All the children had recently deteriorated notably and had poor exercise tolerance. The older children had stopped attending school. Three children with IPAH had had syncopal attacks. Three children with chronic lung disease were oxygen dependant. The mean age at the start of treatment was 8.03 years for IPAH and 8.3 years for secondary PH. There was a female predominance in IPAH but not in secondary PH. Table 1​1 presents medications the children were receiving when they started receiving bosentan. Seven children with IPAH and two with secondary PH were receiving intravenous epoprostenol and deteriorating on a mean dose 39 ng/kg/min when treatment with bosentan was started. Table 1​1 summarises the ECG and transthoracic echocardiographic findings.

Table 1Summary of patient demographics and baseline characteristics

	Idiopathic PAH (n=20)	Secondary PH (n=20)
Age at treatment (years)
Mean	8.03	8.3
Range	1.2–17	0.6–16
Boys:girls	5:15	9:11
Ethnicity
White	19	18
Afro‐Caribbean	0	2
Asian	1	0
Weight (kg)	27.5 (8–70)	23.9 (6.8–59.3)
WHO functional class
II	1	0
III	11	13
IV	8	7
ECG findings
Sinus rhythm	20	18*
Right axis deviation	20	14†
RV hypertrophy with strain	15	9
Echocardiography
Tricuspid jet velocity (m/s)	4.6	4.14
Poor RV function	12	5
Atrial communication	11	5
Cardiac catheterisation
PAP>SAP	9	3
PAP=SAP	7	7
PAP<SAP	4	8
PVR (unitsm2)	21.7 (5.6–42.8)	18.0 (4.9–49)‡
Treatment at start of study
Nocturnal oxygen	20	20
Diuretics	5	6
Nifedipine	0	4§
Sildenafil	2	4
Epoprostenol	7	2
Anticoagulation	12¶	2
Duration of treatment (months)	13.1 (3–24)	12.2 (2–22)

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*One junctional rhythm, one paced; †five superior axis, one paced; ‡n=18; §three patients had systemic hypertension associated with connective tissue disease; ¶six aspirin, six warfarin.

PAH, pulmonary arterial hypertension; PAP, pulmonary arterial pressure; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RV, right ventricular; SAP, systemic arterial pressure; WHO, World Health Organization.

Table 2Idiopathic PAH clinical summary

Patient	Sex	Age (years)	Mean PAP (mm Hg)	PVR (unitsm2)	Pre‐epo	Treatment duration (months)	Epo added	WHO class		Six minutes walk		Weight (kg)
								Baseline	Change with bosentan	Baseline	% Change with bosentan	Baseline	% Change with bosentan
1(died)	F	1.2	31	12.3	No	4	No	IV				8	2.5
2	M	1.2	91	23.9	No	10	No	III	0			8.5	18
3	F	2.3	71	33	No	20	Yes	IV	0			12.8	14
4	M	2.7	89	38.9	Yes	15	No	IV	−1			9	33
5	F	3.4	74	18.6	No	19	No	III	0			10.3	30
6	F	3.9	65	42.8	No	14	Yes	III	1			16.3	3
7	F	4.1	25	12	No	11	Yes	III	1			14.3	10.4
8	M	4.3	54	13.5	No	18	Yes	IV	0			17.4	4
9	F	5.4	50	14.6	No	22	No	III	0			17.4	19
10	F	5.5	71	23	No	18	Yes	IV	0			15.7	28
11	M	7.2	66	18.6	Yes	3	No	III	−1	262	−14	20.9	−3.3
12	F	7.8	68	30	Yes	11	No	III	−1	180	83	17.1	−2.9
13	M	9.75	59	18.5	Yes	21	No	III	0	315	−1.9	28.8	13.8
14	F	12.4	68	16.1	No	7	No	III	0	334	−43	31	−2.5
15	F	12.5	61	16.9	No	11	No	III	−1	250	92	57.5	12.8
16	F	13.7	49	18	No	4	No	IV	−1	430	−2.3	55	1.8
17	F	14.6	25	5.6	Yes	9	No	II	0	300	21.3	52.6	−7.4
18	F	15.5	51	12.5	No	12	No	III	−1	140	157	51.3	−2.1
19	F	16.2	88	27	Yes	24	No	IV	−1	80	275	36.9	19
20	F	17	73	39	Yes	10	No	IV	−1	160	−0.6	70	−1.1

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F, female; M, male; pre‐epo, receiving epoprostenol before treatment with bosentan.

Table 3Secondary PH clinical summary

Patient	Sex	Age (years)	Diagnosis	Mean PAP (mm Hg)	PVR (unitsm2)	Treatment duration (months)	WHO class		Six minutes walk		Weight (kg)
							Baseline	Change	Baseline	% Change	Baseline	% Change
1	F	1.7	AVSD (E)	57	12	22	III	−1			8.7	18
2	M	2.7	TGA/Rastelli	37	36.1	22	IV	0			10	55
3	F	4.2	AVSD, po	38	4.9	16	III	−1	240	76	15.3	16
4	F	4.3	AVSD, po	–	20	7	III	0			15	11
5	M	5.8	TGA, VSD Switch	57	9.4	12	III	−1	110	183.5	13.4	6.7
6	F	10.1	AVSD (E)	83	36.9	17	III	0	80	125	27.9	12
7	F	11.3	TA,VSD (E)†	38	18.7	11	IV	−1	210	24.5	18.5	19
8	M	14.2	TAPVD, po	53	13.3	19	IV	−1	310	36	25.8	9.26
9	M	14.3	TGA/Senning	51	8.1	18	III	−1	290	82	59.3	17
10	M	15.1	DORV (E)	72	17.3	11	III	0	80	127.5	44.1	7.5
11*	F	15.2	TGA/Senning	53	18.4	16	IV	−1	160	187.5	42.1	7.7
12	F	15.7	pAVSD, po	49	13.2	7	III	0	400	7.5	31	4.5
13	F	0.6	CLD	–	–	2	IV	0			6.8	25
14	F	1.9	CLD	32	10.1	19	III	−1			9.3	0
15	M	2.4	CLD	78	49	12	III	−1			12	29
16*	M	3.3	Systemic sclerosis + SAH	43	8	8	III	0			9.6	−6.7
17	M	7.3	Diffuse interstitial lung disease + SAH	48	19.1	6	IV	0			33.5	7.2
18	M	8.1	Cutis marmorata	43	8.25	5	III	−1	312	33.3	19.9	22.4
19	F	12.25	CT disorder/pulmonary fibrosis + SAH	–	–	9	IV	–1			32.8	19.6
20	F	16	HIV	80	22.1	6	III	0	340	−5.8	44.4	4.95

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*Taking epoprostenol at start; †repaired truncus arteriosus with interrupted left pulmonary artery and residual ventricular septal defect (VSD).

AVSD, atrioventricular septal defect; CLD, chronic lung disease; CT, connective tissue; DORV, double outlet right ventricle; E, Eisenmenger's syndrome; pAVSD, partial atrioventricular septal defect; po, postoperative; SAH, systemic arterial hypertension; TA, truncus arteriosus; TAPVD, total anomalous pulmonary venous drainage; TGA, transposition of the great arteries.

In the group with IPAH signs of right atrial and right ventricular hypertrophy were invariably present on the ECG, and 75% of patients had an RV strain pattern. Echocardiography showed right ventricular hypertrophy in all children and systolic function was impaired in 60%. A tricuspid regurgitant jet was invariably present and the velocity exceeded 4 m/s in 95% of children. Pulmonary regurgitation was present in 52%.

An atrial communication was present in 55% of children, either a patent foramen ovale, secundum atrial septal defect, or atrial septostomy. Five children had had a septostomy, including one done for recurrent syncope at the time bosentan was introduced. At cardiac catheterisation (​(tablestables 1 and 2​2),), the pulmonary arterial pressure was similar to the systemic arterial pressure or higher in most children. The mean PVR, measuring oxygen consumption, was between 5.6 and 42.8 unitsm² (mean 21.7 unitsm²). Ten children were aged 5 years or less and the PVR in this group was as great as that in the older children (23.26 v 20.22 unitsm²) The six children in WHO class III and IV already being treated with epoprostenol had a mean PVR of 28.7 unitsm², which was not significantly different from that of the rest of the group. Pulmonary vascular reactivity was assessed by the response to an increase in inspired oxygen concentration and administration of inhaled nitric oxide. No child had a positive response.

In the group with secondary PH ECG showed signs of hypertrophy in the subpulmonary ventricle, with a strain pattern in 45% of all patients. Echocardiography showed hypertrophy of the subpulmonary ventricle in all and impaired systolic function in 60% of the children. A tricuspid regurgitant jet was invariably present, with a velocity exceeding 4 m/s in 95% of children. Pulmonary regurgitation was present in 52%. At cardiac catheterisation (​(tablestables 1 and 3​3),), all patients had severe PH and the mean PVR was 18 unitsm² (range 4.9–49 unitsm²). No child had a positive vasodilator response.

RESULTS

The drug was well tolerated by all patients, including those receiving simultaneous epoprostenol. Liver function tests remained within normal limits in all but one patient who had slightly increased aspartate aminotransferase to less than twice the upper limit of normal. The other adverse effects previously noted in a small proportion of adult patients receiving bosentan, including headache, dizziness, cough, dyspnoea, and flushing, were not encountered in the children.¹⁰ The study included four patients with Eisenmenger's syndrome and none of these patients experienced a significant fall in systemic arterial oxygen saturation. The ECG and echocardiographic findings did not change significantly in any patient during the course of the study. The children have not been recatheterised.

Outcome in children with IPAH

Of the 11 children receiving bosentan as sole treatment, five subsequently needed to be given epoprostenol in addition to bosentan (table 2​2).). All were 5 years old or less. Three of the five children initially improved on bosentan, two returning to school, but all five eventually deteriorated clinically and treatment with epoprostenol was started after a mean of four months (range 2–6 months).One of these children also had an atrial septostomy for recurrent syncope. One child died suddenly after three months' treatment (patient 1). Thus, only five of 11 patients continued to receive bosentan as sole treatment.

At the time treatment with bosentan was started, seven of 20 patients were already receiving epoprostenol. After the addition of bosentan, six improved clinically and one has been taken off epoprostenol (patient 17). Two of the 20 patients (2 and 16) receiving sildenafil before starting bosentan also improved with the addition of bosentan.

All but one patient were in WHO class III and IV at the start of treatment. A score shift indicated improvement in eight patients but overall classification did not change significantly (p = 0.1) (fig 1​1).). The 10 older children performed a six minute walk test. The mean distance walked was 245 m (range 80–430 m). The group improved by a mean of 68 m (95% confidence interval 25 to 161 m), a 57% improvement, which was not significant. Five of the 10 children did, however, improve substantially in exercise capacity (mean improvement 176.8 m) (table 2​2,, fig 1​1).). Of these 20 patients, before treatment six were below normal weight for age and sex and 14 were within two standard deviations of the normal. These relations did not change with treatment (p = 0.55). Of the older 10 patients only four gained weight and the mean gain was only 3%. In the 10 younger patients in whom weight gain was taken as a marker of improvement, mean weight improved by 2.15 kg (p = 0.01), a mean gain of 16%. Improvement in neither weight nor six minute walk test correlated with PVR.

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Figure 1World Health Organization (WHO) classification and results of the six minute walk test before and after treatment with bosentan in patients with idiopathic pulmonary arterial hypertension (IPAH) and secondary pulmonary hypertension (PH).

In summary, in the group with IPAH all children were deteriorating clinically when treatment with bosentan was started and all except one were stabilised (table 2​2).

DISCUSSION

This observational study reporting our experience of treating 40 children with severe, symptomatic PAH with bosentan is encouraging. The drug was given as first line treatment to 25 children and to another 15 who were deteriorating on their existing treatment. Six children did not maintain improvement with bosentan treatment and another specific treatment was added. With or without an additional treatment, of 20 children with IPAH 19 achieved stabilisation and clinical benefit and in 20 children with secondary PH there was objective evidence of clinical improvement. The drug was well tolerated by all patients, including those with Eisenmenger's syndrome. The major limitation of this study is the relatively small number of children treated, making analysis of outcome impossible with respect to disease aetiology in children with secondary PH.

It was encouraging that 20 children with IPAH achieved stability and even some improvement, given the appalling prognosis in this disease.^3,13 The mean PVR at the start of treatment was higher in the present study than the baseline resistance reported in previous trials of bosentan in adults.^10,14 Finding that the resistance was as high in children < 5 years of age as in the older children indicates the aggressive nature of the disease in the very young and supports the contention that the resistance is high from birth in some patients. After treatment, however, we found that the mean distance walked in six minutes by the 10 older children had not decreased with time and the weight of the younger children had not decreased; in fact, both had increased. Nor had the ECG or echocardiographic findings deteriorated any further. Among the 11 children given bosentan as first line treatment five remained well with bosentan monotherapy. In a large recent adult study 85% of patients in WHO class III and IV remained alive and well with bosentan monotherapy at one year.¹⁵ Five of our other patients improved initially, deteriorated after a mean of four months, and sustained the improvement after the addition of intravenous epoprostenol. We noticed that the children could deteriorate suddenly and unexpectedly and they were all monitored closely. The variability in response presumably reflects the state of disease at the onset of treatment and varying rates of disease progression. The findings in this small study are similar to those in an adult study of 169 patients in which the Kaplan‐Meier estimate of survival at one year was 96% for patients given bosentan as first line treatment with the later addition of other specific treatments as indicated.¹⁵

Seven children with IPAH deteriorating when taking what were considered to be adequate doses of epoprostenol improved when given bosentan. Children tolerate and indeed need higher doses of epoprostenol than adults but, since aggressive uptitration in adults can lead to high output cardiac failure, we tried to avoid this complication in our paediatric patients.¹⁶ Pharmacokinetic interaction is unlikely, since the drugs have different metabolic and excretory pathways and the pharmacokinetics of bosentan are not affected by concomitant treatment with epoprostenol.^12,17,18 One patient with a PVR of 5.6 unitsm² during long term treatment with low dose epoprostenol was taken off the drug as has previously been reported.^19,20

Thus, treatment with bosentan was beneficial in 95% of the children with IPAH, but combined treatment with epoprostenol was necessary in 60% of patients. A better outcome might have been achieved had the drugs been given simultaneously from the beginning, particularly as we were treating children, in whom the pulmonary vasculature is remodelling rapidly even in the normal child. In a recent small adult study lasting 16 weeks those receiving both treatments tended to have a greater clinical and haemodynamic benefit but the trend did not reach significance.²¹

In children with secondary PH bosentan produced a significant improvement in WHO class, exercise capacity as reflected in the six minute walk test, and weight gain. Eight children with congenital heart disease had had a technically successful intracardiac repair. Acceleration of pulmonary vascular disease after cardiac repair is well recognised and the children in the present study were deteriorating rapidly until treatment with bosentan was started. Given the similarities in pulmonary vascular pathology it is logical to offer them the same treatment as children with IPAH are given. One child was already being treated with epoprostenol, known to achieve clinical and haemodynamic improvement in such patients, but was deteriorating until he was also treated with bosentan.³ Four children had Eisenmenger's syndrome and showed evidence of clinical improvement after treatment, with no deleterious effects such as a fall in systemic arterial pressure or arterial oxygen saturation. The six minute walk test showed an improvement in the distance walked in the three children old enough to do the test as it did in the 10 adults with Eisenmenger's syndrome recently reported by Gatzoulis et al.²² Three severely symptomatic children had chronic lung disease and three children with connective tissue disease also had pulmonary fibrosis. After treatment with bosentan four of these six children had a beneficial shift in WHO class, their oxygen requirements decreased, and one child with systemic sclerosis was taken off epoprostenol. The patient with HIV improved initially with bosentan treatment but it became necessary to add epoprostenol. Both drugs are efficacious in adults with HIV.^23,24 Four children received sildenafil in addition to bosentan, before it was shown that bosentan decreases the plasma concentration of sildenafil.²⁵

In assessing the response to bosentan several issues that are specific to children need to be considered. In most adult trials of bosentan exercise capacity as reflected in the six minute walk test has been taken as the primary end point, but its use is obviously restricted by age. It has been shown to be reliable in children and was previously found to be reliable in children with PH aged 7 years and older.^20,26,27 Nor is quality of life assessment as straightforward as it is in adults, reflecting as it does an indirect assessment of how the child is feeling. We found weight to be particularly useful as an indicator of response and well being in young children. In the present study the ECG and echocardiogram were helpful in that we did not find evidence of deterioration in cardiac performance but they gave us no indication as to how bosentan might have improved performance, if at all.

ACKNOWLEDGEMENTS

Abbreviations

Footnotes

References