Table 2.

Major trials using endothelin receptor antagonists in pulmonary arterial hypertension

Reference (Sponsor)	Trial design	Drug (dosage)	Duration (weeks) (study name)	Populations	Functional class	Na	Primary endpoint	Primary effect	Secondary endpoints achieved	Liver enzymesb
Channick 2001 (Actelion)	DBPC	Bosentan (62.5 mg bid × 4 weeks, 125 mg bid) or placebo	12 weeks	IPAHc, Scleroderma	III	32	6MWDd	Yes	Functional Class Clinical Worsening Hemodynamics Borg Scale	–
Rubin LJ 2002 (Actelion)	DBPC	Bosentan 125 mg, 250 mg bid or placebo	16 weeks| (BREATHE-1)	IPAH, CTDe	III, IV	213	6MWD	Yes	Functional Class Clinical Worsening Borg Scale	–
Galie N 2003 (Actelion)	–	Bosentan 125 mg, 250 mg bid or placebo	16 weeks (BREATHE-1 Echo substudy)	IPAH, CTD	III, IV	56	Echo and Doppler parameters	Yes	Echo parameters	–
Sitbon 2003 (Actelion)	–	Bosentan 125 mg bid	>1 year	IPAH, Scleroderma	III	29	Safety	Yes	Functional Class Hemodynamics 6MWD	–
McLaughlin 2005 (Actelion)	–	Bosentan 125 mg bid	>2 year	IPAH, CTD	III, IV	169	Survival	Yes	Survival Hemodynamics	14.9%
Barst 2003 (Actelion)	–	Bosentan weight based	12 weeks BREATHE-3	Pediatric IPAH CHD	II, III	19	Hemodynamics	Yes	Functional Class	–
Sitbon 2004 (Actelion)	–	Bosentan 125 mg bid	16 weeks BREATHE-4	HIV	III, IV	16	6MWD	Yes	Functional Class Hemodynamics Quality of Life Echo parameters	–
Galie N 2006 (Actelion)	DBPC	Bosentan 125 mg bid	16 weeks BREATHE-5	Eisenmenger	III	37	Pulmonary vascular resistance	Yes	Functional Class Hemodynamics	–
Barst 2004 (ICOS/Encysive)	DBPC	Sitaxsentan 100–300 mg qd	12 weeks STRIDE-1	IPAH, CTD, CHDg	III	118	6MWD	Yes	Functional Class Hemodynamics	0% at 100 mg dose
Langleben 2004 (Encysive)	–	Sitaxsentan 100 to 300 mg qd	1 year STRIDE-1XC	IPAH, CTD, CHD	II, III	11	Safety	Yes	Functional Class Hemodynamics	–
Barst 2006 (Encysive)	DBPC*	Sitaxsentan 50 mg or 100 mg qd or bosentan 125 mg bid	18 weeks STRIDE-2	IPAH, CTD, CHD	II, III, IV	183	Change in peak VO2	Yes for 300 mg dose	Functional Class 6MWD	3% sitaxsentan 100 mg, 11% bosentan
Pulido 2006 (Encysive)	DBPC	Sitaxsentan 50 mg or 100 mg qd	18 weeks STRIDE-4	IPAH, CTD, CHD	II, III, IV	64	6MWD	Yes in 100 mg dose	Functional Class Borg Scale	3%
Benza 2006 (Encysive)	–	Sitaxsentan 100 mg QD or bosentan 125 mg bid	52 weeks STRIDE-2X	IPAH, CTD, CHD	II, III	Sitaxsentan 145, bosentan 84	Safety	Yes	Functional Class Clinical Worsening Survival	4% sitaxsentan 14% bosentan
Benza 2005 (Encysive)	–	Sitaxsentan 100 mg qd	12 weeks STRIDE-6	IPAH, CTD, CHD	II, III	35	Safety	Yes	Borg Scale
Galie 2005 (Myogen)	DB	Ambrisentan 1, 2.5, 5, or 10 mg QD	24 weeks	IPAH, CTD, HIV, anorexigen	II, III	64	6MWD	Yes	Functional Class Hemodynamics Borg Scale	3%
Oudiz 2006 (Myogen)	DBPC	Ambrisentan 5 mg or 10 g qd	12 weeks ARIES-1	IPAH, CTD, HIV, anorexigen	II, III	124	6MWD	Yes		0%
Olschewski 2006 (Myogen)	DBPC	Ambrisentan 2.5 mg or 5 mg qd	12 weeks ARIES-2	IPAH, CTD, HIV, anorexigen	II, III, IV	124	6MWD	Yes	Functional Class Clinical Worsening Borg Scale Quality of Life	0%

^aN = number of subjects enrolled.

^bAbnormal liver function test were considered above 3x upper limit of normal.

^cIPAH = idiopathic pulmonary arterial hypertension.

^d6MWD = 6-minute walk distance.

^eCTD = connective tissue disease.

^fCHD = congenital heart disease.

^gDB = double-blind.

^hPC = placebo-controlled.

ⁱDBPC* = double-blind only for sitaxsentan arms.