Table 2. Comparison of health-related quality of life (HRQoL) outcomes in pulmonary arterial hypertension (PAH) clinical trials.

Drug	First author [ref.]	Comparator background	Patients n	Baseline NYHA FC	HRQoL measure	Duration weeks	Positive outcome components	p-value
Target: endothelin pathway
Ambrisentan	Galiè [36]	versus placebo	202 ARIES-1	I (2%)# II (38%)# III (55%)# IV (5%)#	SF-36	12	Physical functioning	0.005¶
			192 ARIES-2
Bosentan	Galiè [60]	versus placebo (+/- sildenafil)	185	II (100%)#	SF-36	24	Health transition index	0.0244+
Macitentan	Mehta [73]	versus placebo (+/-PDE5i or prostanoid)	742	I (<1%)# II (52%)# III (46%)# IV (2%)#	SF-36v2	6 months	PCS, MCS and in seven out of eight domains	<0.05§
						EOT	PCS	3 mg 0.008ƒ 10 mg 0.001##
							MCS	3 mg 0.085¶¶ 10 mg 0.053++
Target: nitric oxide pathway
Riociguat	Ghofrani [74]	versus placebo (+/- prostanoid or ERA)	443	I (3%)# II (42%)# III (53%)# IV (1%)# Missing (<1%)	EQ-5D§§	12 (+4)	No significant improvement	0.07
					LPHƒƒ		Nominal improvement seen versus placebo	0.002
Sildenafil	Pepke-Zaba [75]	versus placebo (+ background therapy)	278	I (<1%)# II (39%)# III (58%)# IV (3%)#	SF-36	12	Physical function General health Vitality	<0.001 <0.001 <0.05
					EQ-5D		Utility index Current health status	<0.01
	Sastry [76]	versus placebo	22	II (82%) III (18%)	CHFQ	6	Dyspnoea Fatigue Emotional function	0.009 0.04 0.06
	Simonneau [77]	versus placebo (+ epoprostenol)	267	I (1%)# II (25%)# III (66%)# IV (6%)# Missing (2%)	SF-36v1	16	Physical function Physical role General health Vitality Social functioning Mental health	0.003 0.02 <0.001 <0.001 0.049 0.001
Tadalafil	Pepke-Zaba [78]	versus placebo (+/- bosentan)	405	I (1%)# II (32%)# III (65%)# IV (2%)#	SF-36	16	Physical function### Role physical Bodily pain General health Vitality### Social function###	<0.01¶¶¶ <0.01### <0.01### <0.01### <0.01### <0.001###
					EQ-5D		EQ-5D VAS EQ-5D UK utility	0.05 0.0001
Target: prostacyclin pathway
Beraprost	Barst [57]	versus placebo	116	II (53%)# III (47%)#	MLHFQ		No improvement shown	ns/data not shown
Epoprostenol	Barst [34]	versus conventional therapy	81	III (74%) IV (26%)	CHFQ	12	Dyspnoea Fatigue Emotional function Mastery	+++ p<0.01
					NHP		Emotional reaction Sleep
					Dyspnoea-fatigue rating
Iloprost (inhaled)	Olschewski [38]	versus placebo	203	III (59%) IV (41%)	EQ-5D	12	EQ-5D VAS	0.026§§§
					SF-12		No improvement shown	ns
Treprostinil	McLaughlin [61]	versus placebo (+ bosentan or sildenafil)	235	III (98%) IV (2%)	MLHFQ	12	Global score Physical score	0.027ƒƒƒ 0.037

NYHA: New York Heart Association; FC: functional class; ARIES: Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies; SF: short-form health survey; PDE5i: phosphodiesterase type-5 inhibitors; PCS: physical component summary; MCS: mental component summary; EOT: end of treatment; ERA: endothelin receptor antagonist; EQ-5D: EuroQol 5D questionnaire; LPH: Living with Pulmonary Hypertension questionnaire; CHFQ: chronic heart failure questionnaire; VAS: visual-analogue scale; MLHFQ: Minnesota Living with Heart Failure questionnaire; ns: nonsignificant; NHP: Nottingham Health Profile. ^#: World Health Organization FC; ^¶: for combined ambrisentan groups (2.5 and 5 mg), improvements in physical function were noted for 2.5 mg (p = 0.005) and 5 mg (p = 0.040), similar trends were observed without statistical significance for 5 and 10 mg of ambrisentan; ⁺: SF-36 as compared with relative risks (bosentan versus placebo) and the treatment effect was tested with Fisher’s exact test, a higher proportion of patients on bosentan (57%) versus placebo (38%) improved their SF-36 at 24 weeks (p = 0.02) (HRQoL was an exploratory end-point only); ^§: except for general health perception; ^ƒ: hazard ratio (HR) 0.70 (95% CI 0.54–0.92); ^##: HR 0.65 (95% CI 0.50–0.85); ^¶¶: HR 0.81 (95% CI 0.63–1.03); ⁺⁺: HR 0.79 (95% CI 0.61–1.01); ^§§: scores range from -0.6 to 1.0, higher scores indicate better QoL; ^ƒƒ: scores range from 0 to 105, higher scores indicate worse QoL; ^###: were also improved in the 20 mg group; ^¶¶¶: ANCOVA was used to evaluate changes from baseline to week 16 for SF-36 and EQ-5D, no adjustment of significance values for multiple testing was performed; ⁺⁺⁺: Hodges–Lehmann estimate was used to estimate the true median changes from baseline, whether statistical analysis was properly corrected for multiple comparisons (e.g. for each of the CHFQ and NPH domains) was not described; ^§§§: ANCOVA was used to compare score at baseline and at the end of study; ^ƒƒƒ: Hodges–Lehmann estimates, whether statistical analysis was properly corrected for multiple comparisons (e.g. for each of the MLHFQ domains) was not described. Reproduced from [79] with permission from the publisher.