Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension

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FIGURE 1
Patient disposition. ^#: one patient randomly assigned to receive placebo did not receive the study drug.
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FIGURE 2
Time to primary end-point event up to the end of the study. Kaplan–Meier estimates for the time to first primary end-point event (death from any cause, hospitalisation for pulmonary arterial hypertension (PAH) or start of intravenous prostanoid therapy, atrial septostomy, lung transplantation, or worsening PAH) show a treatment effect in favour of bosentan versus placebo (hazard ratio 0.831, 97.31% CI 0.582–1.187; p=0.2508 by the log-rank test).
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FIGURE 3
Time to primary end-point event by subgroup. For geographical region, one patient from Saudi Arabia was excluded from the analysis. Error bars represent 95% confidence intervals. IPAH: idiopathic pulmonary arterial hypertension; FPAH: familial pulmonary arterial hypertension; WHO: World Health Organization.
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FIGURE 4
Change from baseline in 6-min walk distance at 16 weeks. The difference between the groups was 21.8 m (95% CI 5.9–37.8 m, p=0.0106) by Wilcoxon rank-sum test in favour of bosentan. Data are presented as mean±sem.

TABLE 1

Baseline characteristics in placebo and bosentan groups

	Placebo	Bosentan	All
Patients n	175	159	334
Sex
Female	128 (73.1)	125 (78.6)	253 (75.7)
Male	47 (26.9)	34 (21.4)	81 (24.3)
Age years
Mean±sd	54.7±15.7	52.9±15.4	53.9±15.6
Median (interquartile range)	56.0 (41.0–68.0)	55.0 (40.0–65.0)	55.0 (40.0–66.0)
BMI^# kg·m⁻²
Mean±sd	29.1±6.95	28.5±6.83	28.8±6.9
Median (interquartile range)	28.2 (24.5–32.8)	27.5 (23.9–32.2)	28.0 (24.1–32.8)
Geographical region
USA	83 (47.4)	73 (45.9)	156 (46.7)
Europe	56 (32.0)	50 (31.4)	106 (31.7)
Brazil	35 (20.0)	36 (22.6)	71 (21.3)
Saudi Arabia	1 (0.6)		1 (0.3)
Time from PAH diagnosis months
Mean±sd	26.2±51.2	25.3±47.3	25.7±49.4
Median (interquartile range)	11.4 (6.0–24.9)	12.2 (6.6–28.4)	12.1 (6.3–26.0)
Aetiology of PAH
Idiopathic	114 (65.1)	99 (62.3)	213 (63.8)
Familial	2 (1.1)	3 (1.9)	5 (1.5)
Connective tissue disease	45 (25.7)	43 (27.0)	88 (26.3)
Repaired congenital shunts	11 (6.3)	9 (5.7)	20 (6.0)
Drugs and toxins	3 (1.7)	5 (3.1)	8 (2.4)
6-min walk distance m
Mean±sd	357.6±73.1	363.1±78.5	360.3±75.7
Median (interquartile range)	372.0 (305–410)	385.0 (306–423)	375.5 (306–416)
WHO functional class
II	69 (39.4)	71 (44.7)	140 (41.9)
III	104 (59.4)	88 (55.3)	192 (57.5)
IV	2 (1.1)		2 (0.6)
NT-proBNP^¶ pmol·L⁻¹
Mean±sd	170.1±239.4	189.7±384.0	179.6±317.2
Median (interquartile range)	56.6 (21.6–208.5)	54.3 (19.4–201.0)	54.9 (19.7–202.6)
Baseline sildenafil dose mg
Mean±sd	81.1±45.1	77.8±48.5	79.6±46.7
Median (interquartile range)	60 (60–75)	60 (60–60)	60 (60–60)

Data are presented as n (%) unless otherwise stated. BMI: body mass index; PAH: pulmonary arterial hypertension; WHO: World Health Organization; NT-proBNP: N-terminal pro-brain natriuretic peptide. ^#: placebo, n=172; bosentan, n=157. ^¶: placebo, n=117; bosentan, n=110.

TABLE 2

Primary end-point events in the placebo and bosentan groups

	Placebo	Bosentan
Patients n	175	159
Primary end-point event	90 (51.4)	68 (42.8)
Worsening of PAH^#	52 (29.7)	32 (20.1)
*Hospitalisation for PAH or start of i.v.* prostanoid therapy**	20 (11.4)	25 (15.7)
Death	18 (10.3)	10 (6.3)
Atrial septostomy	0 (0.0)	1 (0.6)
Lung transplantation	0 (0.0)	0 (0.0)

Data are presented as n (%) unless otherwise stated. Events listed are the first confirmed morbidity/mortality events. PAH: pulmonary arterial hypertension. ^#: worsening PAH was 1) “moderately worse” or “markedly worse” symptoms and requirement for addition of PAH therapy (initiation of a subcutaneous or inhaled prostanoid, or transfer to open-label bosentan), or 2) “no change” or “mildly worse” symptoms, and requirement for addition of PAH therapy and deterioration in 6-min walk distance >20% from the previous visit or >30% from the baseline visit.

TABLE 3

Secondary end-points

	Placebo	Bosentan	*Treatment effect versus* placebo**
Patients n	175	159
Change in WHO functional class from baseline to 16 weeks			Relative risk of improvement^# 0.98 (95% CI 0.60–1.61, p=1.000^¶)
Worsened	17 (9.7)	13 (8.2)
Unchanged	130 (74.3)	121 (76.1)
Improved	28 (16.0)	25 (15.7)
Time to death, hospitalisation for PAH, atrial septostomy or lung transplantation up to the end of the study			Hazard ratio 0.963 (95% CI 0.673–1.380, p=0.8385⁺)
Patients	67 (38.3)	54 (34.0)
Time to death from any cause up to the end of the study			Hazard ratio 0.855 (95% CI 0.544–1.344, p=0.4974⁺)
Patients	44 (25.1)	33 (20.8)

Data are presented as n (%) unless otherwise stated. WHO: World Health Organization; PAH: pulmonary arterial hypertension. ^#: versus no improvement; ^¶: Fisher's exact test; ⁺: log-rank test.

TABLE 4

Exposure, safety and tolerability during double-blind treatment period

	Placebo	Bosentan
Patients n	174^#	159
Exposure to double-blind study drug months
Mean±sd	30.7±24.31	26.4±20.99
Median (interquartile range)	23.3 (0.3–85.7)	22.7 (0.0–86.7)
Variable
Patients with adverse events	159 (91.4)	144 (90.6)
Patients with serious adverse events	102 (58.6)	73 (45.9)
Patients with adverse events leading to discontinuation of double-blind treatment	22 (12.6)	39 (24.5)
Patients with adverse events
Worsening of pulmonary arterial hypertension	61 (35.1)	39 (24.5)
Oedema, peripheral	28 (16.1)	30 (18.9)
Dyspnoea	26 (14.9)	25 (15.7)
Headache	24 (13.8)	24 (15.1)
Upper respiratory tract infection	30 (17.2)	22 (13.8)
Cough	21 (12.1)	22 (13.8)
Chest pain	16 (9.2)	22 (13.8)
Diarrhoea	19 (10.9)	19 (11.9)
Pneumonia	13 (7.5)	18 (11.3)
Bronchitis	21 (12.1)	17 (10.7)
Dizziness	18 (10.3)	17 (10.7)
Anaemia	12 (6.9)	17 (10.7)
Nausea	22 (12.6)	16 (10.1)
Urinary tract infection	14 (8.0)	16 (10.1)
ALT increase	8 (4.6)	16 (10.1)
Back pain	23 (13.2)	15 (9.4)
Arthralgia	20 (11.5)	13 (8.2)
Fatigue	20 (11.5)	13 (8.2)
Syncope	12 (6.9)	8 (5.0)
Hypotension	7 (4.0)	0 (0)
Laboratory abnormality^¶
ALT or AST >3×ULN	11 (6.4)	34 (21.8)
ALT or AST >8×ULN	0 (0)	8 (5.1)
Haemoglobin ≤10 g·dL⁻¹	15 (8.8)	14 (9.0)

Data are presented as n (%) unless otherwise stated. ALT: alanine aminotransferase; AST: aspartate aminotransferase; ULN: upper limit of normal. ^#: one patient randomly assigned to receive placebo did not receive the study drug and was excluded from the safety analyses. ^¶: placebo, n=171; bosentan, n=156.