Figures
- FIGURE 1
Patient disposition. Disease progression end-points defined as in GRIPHON [11] and TRITON [8], respectively, up to end of double-blind treatment +7 days. Two patients were excluded from TRITON because their time since diagnosis was over 6 months (183 days). #: Placebo patients in TRITON received placebo, macitentan and tadalafil.
- FIGURE 2
Time to disease progression up to end of treatment period in the pooled dataset: a) main analysis and b) subgroup of patients receiving ERA+PDE-5i combination therapy at randomisation. Kaplan–Meier curves illustrating time from randomisation to first disease progression event up to end of treatment period, defined as end of double-blind treatment +7 days in GRIPHON and end of main observation period +7 days or end of double-blind treatment +7 days in TRITON. Curves are cut when <10% of patients remain at risk (Pocock's rule) [13]. Kaplan–Meier estimates are shown at Months 6, 12 and 24. a) HR estimated using a Cox model which included treatment, age, sex, race, PAH aetiology, region, WHO FC, 6MWD, NT-proBNP and study as covariates. b) HR estimated using a Cox model which included treatment, region, WHO FC at baseline and study as covariates. 6MWD: 6-min walk distance; HR: hazard ratio; ERA: endothelin receptor antagonist; NT-proBNP: N-terminal pro-brain natriuretic peptide; PAH: pulmonary arterial hypertension; PDE-5i: phosphodiesterase-5 inhibitor; WHO FC: World Health Organization functional class.
- FIGURE 3
Time to all-cause death up to end of study for the pooled dataset: a) main analysis and b) subgroup of patients receiving ERA+PDE-5i therapy at randomisation. Kaplan–Meier curves illustrating time from randomisation to all-cause death up to end of study. Curves are cut when <10% of patients remain at risk (Pocock's rule) [13]. Kaplan–Meier estimates are shown at Months 6, 12 and 24. a) HR estimated using a Cox model which included treatment, age, sex, race, PAH aetiology, region, WHO FC, 6MWD, NT-proBNP and study as covariates. b) HR estimated using a Cox model which included treatment, region, WHO FC at baseline and study as covariates. 6MWD: 6-min walk distance; HR: hazard ratio; ERA: endothelin receptor antagonist; NT-proBNP: N-terminal pro-brain natriuretic peptide; PAH: pulmonary arterial hypertension; PDE-5i: phosphodiesterase-5 inhibitor; WHO FC: World Health Organization functional class.
Tables
- TABLE 1
Demographics and baseline characteristics
Characteristic Pooled selexipag Pooled control Patients n 329 320# Female, n (%) 256 (77.8) 249 (77.8) Age years, mean±sd 47.3±15.1 47.0±15.7 Time since PAH diagnosis days, median (Q1–Q3) 24.4 (12.2–82.4) 24.4 (9.2–67.1) PAH aetiology, n (%) Idiopathic 158 (48.0) 174 (54.4) Associated with connective tissue disease 109 (33.1) 102 (31.9) Associated with congenital heart disease 26 (7.9) 24 (7.5) Drug- or toxin-induced 18 (5.5) 7 (2.2) Heritable 13 (4.0) 8 (2.5) Associated with HIV infection 5 (1.5) 5 (1.6) Geographical region, n (%) North America 84 (25.5) 82 (25.6) Rest of the world 245 (74.5) 238 (74.4) BMI kg·m−2, mean±sd 26.9±5.8 26.2±5.9 6MWD m, mean±sd 346.8±96.0 342.3±99.6 NT-proBNP, n (%)¶ Low risk (<300 ng·L−1) 104 (31.6) 84 (26.3) Medium risk (300–1400 ng·L−1) 104 (31.6) 110 (34.4) High risk (>1400 ng·L−1) 116 (35.3) 122 (38.1) WHO FC, n (%) I/II 141 (42.9) 123 (38.4) III/IV 188 (57.1) 197 (61.6) Other PAH therapy+, n (%) 254 (77.2) 238 (74.4) ERA+PDE-5i 145 (44.1)§ 140 (43.8) PDE-5i 88 (26.7) 77 (24.1) ERA 21 (6.4) 21 (6.6) PAH: pulmonary arterial hypertension; HIV: human immunodeficiency virus; BMI: body mass index; 6MWD: 6-min walk distance; NT-proBNP: N-terminal pro-brain natriuretic peptide; WHO FC: World Health Organization functional class; ERA: endothelin receptor antagonist; PDE-5i: phosphodiesterase-5 inhibitor. #: n=318 for 6MWD; n=319 for BMI; ¶: data were missing for five selexipag and four control patients. +: PAH therapy was started >3 months before randomisation, except for the 121 and 123 patients from TRITON who started ERA+PDE-5i therapy at randomisation. §: one TRITON patient received background PDE-5i therapy prior to randomisation.
- TABLE 2
Breakdown of disease progression events
Pooled selexipag Pooled control Patients n 329 320 First disease progression events up to end of treatment period#, n (%) 67 (20.4) 116 (36.3) Hospitalisation for worsening of PAH 29 (8.8) 54 (16.9) Clinical worsening of PAH¶ 18 (5.5) 45 (14.1) Death 14 (4.3) 13 (4.1) Initiation of prostacyclin for worsening of PAH 6 (1.8) 4 (1.3) Deaths up to end of study, n (%) 40 (12.2) 55 (17.2) PAH: pulmonary arterial hypertension; 6MWD: 6-min walk distance; WHO FC: World Health Organization functional class. #: end of treatment period was defined as end of double-blind treatment +7 days in GRIPHON and end of main observation period +7 days or end of double-blind treatment +7 days in TRITON. ¶: disease progression in GRIPHON [11] defined as a decrease from baseline of ≥15% in 6MWD (confirmed by a second test on a different day) accompanied by a worsening in WHO FC (for the patients in WHO FC II or III at baseline) or the need for additional PAH therapy (for the patients in WHO FC III or IV at baseline); clinical worsening in TRITON [8] defined as a post-baseline decrease in 6MWD >15% from the highest 6MWD obtained at/after screening and WHO FC III/IV (both conditions confirmed at two consecutive post-baseline visits 1–21 days apart).
- TABLE 3
Exposure and safety
Pooled selexipag Pooled control Patients n 329 320 Exposure to study treatment months, median (min, max) 16.7 (0.1, 42.0) 13.4 (0.1, 43.2) AEs, n (%) Patients with ≥1 AE 323 (98.2) 307 (95.9) Patients with ≥1 serious AE 140 (42.6) 129 (40.3) Patients with ≥1 AE leading to discontinuation of double-blind study treatment 85 (25.8) 100 (31.3) Number of AEs 2836 2259 Most frequent AEs, n (%)# Headache 208 (7.3) 126 (5.5) Diarrhoea 130 (4.6) 64 (2.8) Nausea 105 (3.7) 51 (2.2) Peripheral oedema 79 (2.8) 76 (3.3) Pain in jaw 68 (2.4) 20 (0.9) Pain in extremity 65 (2.3) 24 (1.1) Vomiting 62 (2.2) 29 (1.3) PAH worsening 53 (1.9) 94 (4.1) Dyspnoea 49 (1.7) 61 (2.7) Myalgia 48 (1.7) 33 (1.5) Arthralgia 44 (1.5) 29 (1.3) Dizziness 41 (1.4) 47 (2.1) Nasopharyngitis 40 (1.4) 34 (1.5) Flushing 38 (1.3) 26 (1.1) Cough 34 (1.2) 37 (1.6) Upper respiratory tract infection 33 (1.2) 46 (2.0) Fatigue 32 (1.1) 33 (1.5) Dyspepsia 32 (1.1) 18 (0.8) Anaemia 31 (1.1) 21 (0.9) Back pain 23 (0.8) 24 (1.1) Nasal congestion 22 (0.8) 24 (1.1) Right ventricular failure 18 (0.6) 26 (1.1) Gastroesophageal reflux disease 16 (0.6) 22 (1.0) AE: adverse event; PAH: pulmonary arterial hypertension. #: calculated based on the number of AEs; includes AEs with a frequency of ≥1% in either group.
Supplementary Material
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Supplementary material 00456-2022.SUPPLEMENT
