Table 8 Endothelin receptor antagonists: randomised trials

Study	Patients					Outcome measures					Side effects	Comments
Channick et al 2001132 R DB PCPbo vs Bos(250) in PAHDuration 12 weeksOutcomes: 1. 6MWD2. Haemodynamics, BDI, FC, TCW	n = 32 (M 4, F 28) (IPAH 27, CTD 5)						Pbo	Bos	p Value		Elevated transaminases: Bos 2 (transient requiring no change in therapy)
		Pbo	Bos			II/III/IV	1/8/2^NS	10/11/0*
	n	11	21			6MWD	349^NS	430**	**
	Age	47	52			RAP	+4.9	−1.3	*
	II/III/IV	0/11/0	0/21/0			mPAP	+5.1	−1.6	**
	6M WD	355	360			PVR	+191	−223	*
	RAP	9.9	9.7			CI	−0.5	+0.5	*
	mPAP	56	54			p values vs baseline in same columnp values Bos vs Pbo (4th column) BDI 1.6 (95% CI 0.0 to 3.1) lower in Bos cf.PboTime to clinical worsening Bos>Pbo*
	PVR	942	896
	CI	2.5	2.4
Rubin et al 2002135 BREATHE-1 R DB PC Pbo vs Bos(250) vs Bos(500) in PAH Duration 16 weeks Outcomes: 1. 6MWD 2. BDI, FC, TCW	n = 213 (M 45, F 168) IPAH 150, CTD 63.					Improvement in FC:					Worsening of pulmonary hypertension — Pbo 19%; Bos (combined) 8%Abnormal hepatic function — Pbo 3%; Bos (combined) 9%	Subgroup analysis of 6MWD: IPAH: Pbo vs Bos (combined) + 51 (NS) SSc: Pbo vs Bos (combined) + 43 (NS)
		Pbo	Bos	Bos			Pbo	Bos	Bos
	Dose	–	250	500		Dose	–	250	500
	n	69	74	70		Imp to II	28%	38%^NS	34%^NS
	Age	47	50	47		Imp to I	0%	3%^NS	1%^NS
	III/I V	65/4	68/6	62/8		Overall	30%	42%^NS
	6M WD	334	326	333			Pbo	Bos	Bos
	RAP	8.9	9.7	9.9		Dose	–	250	500
	mPAP	53	53	57		6MW D	326	353*	379*
	PVR	880	884	1167		BDI	+0.3	−0.1^NS	−0.6**
	CI	2.4	2.5	2.2		Time to clinical worsening Bos>Pbo*
Barst et al 200463 STRIDE-1R DB PCPbo vsSitax(100) vsSitax(300) in PAH Duration : 12 weeksOutcomes: 10% of predicted Vo₂max2. 6MWD, FC, Vo₂ and Ve/Vco₂ at AT, SF36, TCW, haemodynamics	n = 178 (M 37, F 141) IPAH 94, CTD 42, CHD 42						Pbo	Sitax	Sitax		No differences between groups in the total number of adverse events. Incidence of serious adverse events: Pbo 15%; Sitax(100) 5%; Sitax(300) 16%).One death due to worsening PAH in Sitax(300). Most frequently reported clinical adverse events with Sitax were headache, peripheral oedema, nausea, nasal congestion, and dizziness. Significant interaction with warfarin led to significant rises in INR. Elevated transaminases (>3×ULN): Pbo 3%Sitax(100) 0%Sitax(300) 10% (NS)	When data combined with open label extension study, Kaplan–Meier estimate for elevated transaminases (>3xULN) at 9 months 8% for Sitax(100) and 32% for Sitax(300). As milder pts and pts with CHD included in this study unlike BREATHE-1, post hoc analysis examined end points when only pts with IPAH and CTD with baseline 6MW<450 in FC III/IV included. 6MW improvement for Sitax(combined) increased from +34 to +65′
	n = 178 (M 37, F 141) IPAH 94, CTD 42, CHD 42					Dose	–	100	300
		Pbo	Sitax	Sitax		Improved FC	15%	29%**	30%**
	Dose	–	100	300		Worsened FC	7%	0%^NS	2%^NS
	n	60	55	63		6MW	400	416*	407*
	Age	48	45	44		RAP	+1	0^NS	−1*
	II/III/IV	22/36/2	16/39/0	21/42/0		mPAP	0	−3*	−5*
	6MWD	413	394	387		PVR	+49	−221*	−194*
	RAP	8	7	9		CI	0.0	+0.3**	+0.4*
	mPAP	52	54	54		%pred Vo₂max	−0.1	−0.4	+3.0^NS
	PVR	911	1026	946		, * p vs Pbo
	CI	2.4	2.3	2.3		Time to clinical worsening SF-36, Vo₂ and Ve/Vco₂ at AT:
	%pred Vo₂max	48	45	45		No significant differences between groups
Galie et al 2006134 BREATHE-5R DB PC Pbo vs Bos(250) in CHD (aged>12) Duration: 16 weeks Outcomes: 1. Spo₂, PVRI 2. Haemodynamics, 6MWD, FC	n = 54 (M 21, F 33) ASD 13, VSD 36, ASD+VSD 5						Pbo	Bos	p Value		Mean systemic arterial pressure rose by 2.5 in Pbo group and fell by 3.8 mm Hg in Bos group (difference 6.3 mm Hg, p = 0.028). Pbo/Bos(%)Peripheral oedema 6/19 Headache 12/14 Palpitations 0/11Chest pain 0/8(Severe intensity 18/8) Discontinuations 12/5 including 1 episode of elevated transaminases in Bos group	Drop in systemic arterial pressure in Bos group was well tolerated with only one episode of vasovagal syncope after first dose of Bos after 12 h of bed rest.
						II/III/IV	2/14/1^NS	13/23/1^NS
		Pbo	Bos			6MWD	356	375	*
	n	17	37			RAP	+0.4	+0.3	NS
	Age	44	37			LAP	+0.5	+0.4	NS
	II/III/IV	0/17/0	0/37/0			mPAP	+0.5	−5	**
	Spo₂	84	82			PVRI	+155	−317	NS
	6M WD	366	332			SVRI	+379	−373	NS
	RAP	5	6.1			PFI	+0.0	+0.1	**
	LAP	6.5	8.1			SFI	−0.2	+0.9	NS
	mPAP	72	78			p values for FC vs baseline
	PVR I	2870	3425			Spo₂ Pbo corrected effect of Bos +1.0%
	SVR I	3658	3244
	PFI	2.0	1.9
	SFI	2.1	2.7
Denton et al 2006133 R DB PC with OL EPAH CTD pts from extension studies from Channick et al132 and BREATHE-1135 (Bos(250 and 500)) Duration: 2 years	Initial treatment in PC trial	Bos	Pbo			At end of PC trial					Addition of Epo 1 Discontinuations 23 Death 5 Elevated transaminases 7 Worsening PAH 4Withdrawal of consent 2 Hepatitis 2 Anaemia 1 Pneumonia 1 Raised bilirubin 1	Pts with significant interstitial lung disease (forced vital capacity <70% predicted) were excluded.
	n	44	22				Bos	Pbo	p Value
	M/F	6/38	5/17			III/IV	NR	NR
	Age	58	50			6MWD	332	358	NS
	III/IV	42/2	21/1			Event-free survival at 16 weeks: Bos 90 vs Pbo 86%Mean duration of follow-up 1.8 years. Dose NROf 66 pts, 64 entered in to OL E study40 remained on Bos monotherapy at 1.8 years. In this group, FC had improved in 25% and 6MWD increased from 352 to 3671 year survival 86%2 year survival 73%
	SSc	37	15
	SLE	5	3
	Overlap syn	1	3
	Unclassified	1	1
	6MWD	312	361
	RAP	8	8
	mPAP	47	45
	CI	2.4	2.5
	PVR	809	722
Barst et al 2006131 STRIDE-2R DB PCPbo vs Sitax(50) vs Sitax(100) vs Bos(250) open-labelDuration: 18 weeksOutcomes: 1. 6MWD 2. FC, BDI, TCW	n = 245 (M 55, F 190) IPAH 144, CTD 74, CHD 26					Improvement in FC:					Adverse events – no differences between groups. Nasal congestion, fatigue and insomnia reported more frequently in Sitax groups (NS). Discontinuations: Pbo 10% Sitax(50) 7% Sitax(100) 3% Bos 10% (NS) Elevated transaminases (>3×ULN): Pbo 6% Sitax(50) 5% Sitax(100) 3% Bos 11% (NS)	Dividing the study population into four groups may have reduced the power to detect differences between treatment and placebo relating to time to clinical worsening. Open-label Bos arm makes any comparisons with this group problematic
	n = 245 (M 55, F 190) IPAH 144, CTD 74, CHD 26						Pbo	Sitax	Sitax	Bos
		Pbo	Sitax	Sitax	Bos	Dose	–	50	100	250
	Dose	–	50	100	250		10%	NR	13%^NR	NR
	n	62	62	61	60	Improvement or no change in FC:
	Age	53	57	55	49		85%	NR	98%**	NR
	II/III/IV	23/35/4	21/38/3	26/34/1	22/37/1	Worsening FC (p values NR):
	6MWD	321	328	360	337		13%	13%	2%	9%
	mPAP	49	48	45	50	p vs PboTime to clinical worsening and BDI: No significant differences between groups
	PVR	880	800	800	880
	CI	2.4	2.7	2.4	2.4