Management of severe pulmonary arterial hypertension

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Figure 1.
Survival of idiopathic pulmonary arterial hypertension (IPAH) patients in World Health Organization functional class (FC) at baseline IV is extremely poor in a) IPAH (reproduced from [18] with permission from the publisher) and b) pulmonary arterial hypertension associated with connective tissue diseases (reproduced from [9] with permission from the publisher).
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Figure 2.
Patients who remain in World Health Organization function class (FC) IV after treatment is initiated have a poor prognosis. a) Data from the USA. Reproduced from [17] with permission from the publisher. b) Data from Europe. Reproduced from [18] with permission from the publisher.
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Figure 3.
Evidence-based treatment of World Health Organization functional class IV pulmonary arterial hypertension patients. Modified from [5] with permission from the publisher.

Table 1 World Health Organization functional classification (WHO FC) definitions

Class	Definition
WHO FC I	Patients with PH but without resulting limitation of physical activityOrdinary physical activity does not cause undue dyspnoea or fatigue, chest pain or near syncope
WHO FC II	Patients with PH resulting in slight limitation of physical activityThey are comfortable at restOrdinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope
WHO FC III	Patients with PH resulting in marked limitation of physical activityThey are comfortable at restLess than ordinary activity causes undue dyspnoea or fatigue, chest pain or near syncope
WHO FC IV	Patients with PH with inability to carry out any physical activity without symptomsThese patients manifest signs of right-heart failureDyspnoea and/or fatigue may even be present at restDiscomfort is increased by any physical activity

Table 2 World Health Organization functional class (WHO FC) IV patients in randomised clinical trials of pulmonary arterial hypertension

Investigational drug	Trial and publication year	Patients in WHO FC IV at baseline %
Epoprostenol	Barst et al. [20]; 1996	27
Iloprost^#	Olschewski et al. [39]; 2002	42
Treprostinil	Simonneau et al. [40]; 2002	7
Bosentan	Channick et al. [41] (Study 351); 2001	0
	Rubin et al. [42] (BREATHE-1); 2002	8
Ambrisentan	Galiè et al. [43] (ARIES-1); 2008	7
	Galiè et al. [43] (ARIES-2); 2008	2
Sitaxentan	Barst et al. [44] (STRIDE-1); 2004	1
	Barst et al. [45] (STRIDE-2); 2006	4
Sildenafil	Galiè et al. [46] (SUPER-1); 2005	3
Tadalafil	Galiè et al. [47] (PHIRST-1); 2009	2

BREATHE: Bosentan Randomized Trial of Endothelin Antagonist Therapy; ARIES: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Study; STRIDE: Sitaxsentan To Relieve Impaired Exercise; SUPER: Sildenafil Use in Pulmonary Arterial Hypertension; PHIRST: Pulmonary Arterial Hypertension and Response to Tadalafil. ^#: patients were stratified by WHO FC prior to being randomised.