| 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.