Bosentan in the treatment of pulmonary arterial hypertension with the focus on the mildly symptomatic patient

Figures & data

Table 1 The Venice classification of pulmonary hypertension 2003

Group 1. Pulmonary arterial hypertension
1.1. Idiopathic pulmonary arterial hypertension
1.2. Familial pulmonary arterial hypertension
1.3. Pulmonary arterial hypertension associated with:
1.3.1. Collagen vascular disease, eg, scleroderma, systemic lupus erythematosus, rheumatoid arthritis
1.3.2. Congenital systemic-to-pulmonary shunts
1.3.3. Portal hypertension, eg, ethanol induced cirrhosis
1.3.4. HIV infection
1.3.5. Drugs and toxins, eg, fenfluramine
1.3.6. Other (thyroid disorders, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy)
1.4. Associated with significant venous or capillary involvement
1.4.1. Pulmonary veno-occlusive disease (PVOD)
1.4.2. Pulmonary capillary hemangiomatosis (PCH)
1.5. Persistent pulmonary hypertension of the newborn
Group 2. Pulmonary hypertension with left heart disease
2.1. Left sided atrial or ventricular heart disease
2.2. Left sided valvular heart disease
Group 3. Pulmonary hypertension associated with lung disease or hypoxemia
3.1. Chronic obstructive pulmonary disease
3.2. Interstitial lung disease
3.3. Sleep-disordered breathing
3.4. Alveolar hypoventilation disorders
3.5. Chronic exposure to high altitude
3.6. Developmental abnormalities
Group 4. Pulmonary hypertension due to chronic thrombotic, embolic disease, or both
4.1. Thromboembolic obstruction of proximal pulmonary arteries
4.2. Thromboembolic obstruction of distal pulmonary arteries
4.3. Non-thrombotic pulmonary embolism (tumor, parasites or foreign material)
Group 5. Miscellaneous
Eg, sarcoidosis, pulmonary Langerhans’-cell histiocytosis, lymphangiomatosis, granulomatous disease, compression of pulmonary vessels (adenopathy, tumor or fibrosing mediastinitis)

Adapted with permission from Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2004;43 Suppl S: 5S–12S. Copyright © 2004. elsevier.

Table 2 Functional classification of pulmonary hypertension modified after the NYHA functional classification according to the World Health Organization

Class I – Patients with pulmonary hypertension but without resulting limitation of physical activity. Normal physical exertion does not cause undue dyspnea or fatigue, chest pain or near syncope.

Class II – Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.

Class III – Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.

Class IV – Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.

Figure 1 Outline treatment algorithm for pulmonary arterial hypertension (PAH) at a specialist center.

Abbreviations: ERA, endothelin-1 receptor antagonist; FC, functional classification.

Table 3 PAH studies reporting effect of bosentan

First author	Name	Year	N=	Groups	Comparator	Design	Effect vs comparator	P-value
Channick^Citation28	Study 351	2001	32	IPAH; SSc	Placebo	DB R	6MWD +76 m	p < 0.05
Rubin^Citation29	BREATHE-1	2002	213	IPAH; CTD	Placebo	DB R	6MWD +35 m (250 mg)	p < 0.01
Barst^Citation13	BREATHE-3	2003	19		Baseline	OL	mPAP −8 mmHg PVR –300 dynes/s/cm^5
Humbert^Citation30	BREATHE-2	2004	33	IPAH; CTD	Placebo	R	PVR −188 dynes/s/cm^5	ns
Sitbon^Citation12	BREATHE-4	2004	16	HIV	Baseline	OL	6MWD +91 m	p < 0.001
Wilkins^Citation31	SERAPH	2005	26	IPAH; CTD	Sildenafil	R	6MWD −16 m	ns
Barst^Citation32	STRIDE-2	2006	185	IPAH; CTD; CHD	Sitaxentan	OL R	6MWD +1.5 m	ns
Galiè^Citation14	BREATHE-5	2006	54	CHD	Placebo	DB R	PVRI −472 dynes/s/cm^5	p < 0.05
							6MWD +53 m	p < 0.01
Mathai^Citation33		2006	25	IPAH; SSc	Baseline	OL	6MWD +52 m	ns
Denton^Citation34	TRUST	2007	53	CTD	Baseline	OL	12 patients improved FC
Akagi^Citation35		2008	8	IPAH	Baseline	OL	mPAP −13 mmHg	p < 0.05
Galiè^Citation36	EARLY	2008	185	IPAH; CHD; CTD; HIV	Placebo	DB R	6MWD +19 m	ns
							PVR −197 dynes/s/cm^5	p < 0.0001
Jaïs^Citation15	BENEFIT	2008	99	CTEPH	Placebo	DB R	PVR −193 dynes/s/cm^5	p < 0.0001
							6MWD +2 m	ns

Abbreviations: IPAH, idiopathic pulmonary artery hypertension; SSc, scleroderma-associated pulmonary arterial hypertension; CTD, connective tissue disease associatedi pulmonary artery hypertension; HIV, human immunodeficiency virus associated pulmonary artery hypertension; CHD, congenital heart disease associated pulmonary artery hypertension; CTEPH, chronic thromboembolic pulmonary hypertension; DB, double blinded; R, randomized; OL, open label, 6MWD, six-minute walk distance; mPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; FC, functional class.

Table 4 PAH studies including (more than 10) patients in FC II

Author/study	Year	Treatment	Design	Endpoint	Effect	No. FC II	Treat	FC II analysis
Galiè SUPER-1^Citation42	2005	sildenafil	DB R P	6MWD	+42 m p < 0.001	108 of 278	75*	+40 m
Galiè^Citation43	2005	ambrisentan	DB R P	6MWD	+36 m p < 0.0001	23 of 64	17	+58 m
Galie EARLY36	2008	bosentan	DB R P	PVR	−197 p < 0.0001	185 of 185	93	n/a
				6MWD	+19 m ns			n/a
Galiè ARIES^Citation44	2008	ambrisentan	DB R P	6MWD	+43 m	165 of 383	113*	36–55 m
Simonneau UT15^Citation45	2002	trepostinil	DB R P	6MWD	+10 m	53 of 470	25	No
Galiè ALPHABET^Citation46	2002	beraprost	DB R P	6MWD	+15 m	64 of 130	31	No
Barst^Citation47	2003	beraprost	DB R P	VO2 max	p < 0.002	61 of 116	33	No
Barst STRIDE-1^Citation48	2003	sitaxentan	DB R P	VO2 max	+1.1	59 of 178	37	No
Sastry^Citation49	2004	sildenafil	DB X P	Treadmill test	+211s p < 0.0001	18 of 22	18	No
Barst STRIDE-2^Citation32	2006	sitaxentan	DB R P	6MWD	+28 m p < 0.05	92 of 185	47	No
		bosentan		6MWD	+29 m p < 0.05		22	No
Simonneau PACES^Citation50	2008	sildenafil	DB R P	6MWD	+29 m	71 of 267	35*	No

Notes: Treat column refers to the number of patients enrolled in each trial in FC I or II and assigned to treatment arm.

* includes FC I patients.

Abbreviations: DB, double blind; R, randomized; P, placebo-controlled; X, crossover; 6MWD, six-minute walk distance; PVR, pulmonary vascular resistance; FC, functional class.

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