ONLINE APPENDIX
OnlineTable 1: Adverse Events Leading to PAH-Related Hospitalization up to End of Treatment
Adverse event, n (%)
Placebo
(n=249)
Macitentan 3 mg
(n=250)
Macitentan 10 mg
(n=242)
Total patients with at least one
adverse event
Total number of adverse events
PAH worsening
Right ventricular failure
Syncope
Hemoptysis
Chest pain
Respiratory failure
Atrial flutter
Left ventricular failure
Acute right ventricular failure
Dyspnea
Hypotension
Systemic lupus erythematosus
Angina pectoris
Atrial tachycardia
Cardiac arrest
Heart and lung transplant
Hypoxia
Palpitations
Pleural effusion
Acute renal failure
Renal impairment
Respiratory tract infection
Right ventricular dysfunction
Sudden cardiac death
Supraventricular tachycardia
Increased transaminases
Upper gastrointestinal
hemorrhage
Urinary tract infection
Atrial fibrillation
Cardiopulmonary failure
Pneumonia
Presyncope
Renal failure
80 (32.1)
53 (21.2)
46 (19.0)
96
42 (16.9)
38 (15.3)
3 (1.2)
2 (0.8)
–
–
–
2 (0.8)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
64
26 (10.4)
15 (6.0)
4 (1.6)
3 (1.2)
1 (0.4)
2 (0.8)
1 (0.4)
–
1 (0.4)
–
–
1 (0.4)
1 (0.4)
–
1 (0.4)
1 (0.4)
–
1 (0.4)
–
1 (0.4)
1 (0.4)
–
–
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
57
22 (9.1)
18 (7.4)
2 (0.8)
2 (0.8)
2 (0.8)
1 (0.4)
1 (0.4)
1 (0.4)
–
1 (0.4)
1 (0.4)
–
–
1 (0.4)
–
–
1 (0.4)
–
1 (0.4)
–
–
1 (0.4)
1 (0.4)
–
–
–
–
–
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
1 (0.4)
–
–
–
–
–
–
1 (0.4)
–
–
–
–
–
Patients may have had more than one adverse event leading to hospitalization.
Online Table 2: PAH-Related Hospitalizations by Geographic Region Both Unadjusted and Adjusted for
WHO FC at Baseline*
Placebo
Macitentan
3 mg
Macitentan 10
mg
N=30
N=30
N=23
Patients with at least one hospitalization for PAH (n)
1
3
3
Total number of hospitalizations for PAH (n)
1
3
3
Total number of days of hospitalization for PAH (n)
8
14
18
1.9
5.5
6.7
0.3, 13.1
1.8, 17.1
2.1, 20.6
0.15
0.26
0.40
0, 0.46
0, 0.57
0, 0.87
1.1
3.5
5.6
0.1, 9.0
0.9, 14.2
1.5, 20.7
NORTH AMERICA
UNADJUSTED ANALYSES
PAH hospitalization count (PAH hospitalization rate per
100PY; 95% CI)
PAH hospitalization days (mean annual number of PAHrelated hospital days; 95% CI)
ANALYSES ADJUSTED FOR WHO FC AT BASELINE
PAH hospitalization count (PAH hospitalization rate per
100PY; 95% CI)
PAH hospitalization days (mean annual number of PAHrelated hospital days; 95% CI)
0.14
0.29
0.37
0, 0.44
0, 0.63
0, 0.77
WESTERN EUROPE / ISRAEL
N=51
N=42
N=48
Patients with at least one hospitalization for PAH (n)
20
11
5
Total number of hospitalizations for PAH (n)
22
12
6
Total number of days of hospitalization for PAH (n)
216
126
60
30.6
17.3
6.3
20.2, 46.5
9.9, 30.5
2.8, 14.0
UNADJUSTED ANALYSES
PAH hospitalization count (PAH hospitalization rate per
100PY; 95% CI)
3.1
1.8
0.6
1.7, 4.4
0.7, 3.0
0.0, 1.3
25.7
14.5
5.2
16.2, 40.9
8.0, 26.5
2.3, 11.9
2.9
2.0
0.65
1.7, 4.1
0.8, 3.2
0.0, 1.3
N=59
N=63
N=62
Patients with at least one hospitalization for PAH (n)
22
14
14
Total number of hospitalizations for PAH (n)
24
17
20
Total number of days of hospitalization for PAH (n)
275
138
207
24.9
13.6
15.6
16.7, 37.1
8.5, 21.9
10.1, 24.2
2.9
1.1
1.6
1.6, 4.1
0.5, 1.7
0.7, 2.5
22.2
11.1
11.5
14.5, 34.0
6.7, 18.4
7.0, 18.7
2.7
1.2
1.7
1.6, 3.9
0.5, 1.8
0.7, 2.7
N=68
N=71
N=68
20
18
13
PAH hospitalization days (mean annual number of PAHrelated hospital days; 95% CI)
ANALYSES ADJUSTED FOR WHO FC AT BASELINE
PAH hospitalization count (PAH hospitalization rate per
100PY; 95% CI)
PAH hospitalization days (mean annual number of PAHrelated hospital days; 95% CI)
EASTERN EUROPE / TURKEY
UNADJUSTED ANALYSES
PAH hospitalization count (PAH hospitalization rate per
100PY; 95% CI)
PAH hospitalization days (mean annual number of PAHrelated hospital days; 95% CI)
ANALYSES ADJUSTED FOR WHO FC AT BASELINE
PAH hospitalization count (PAH hospitalization rate per
100PY; 95% CI)
PAH hospitalization days (mean annual number of PAHrelated hospital days; 95% CI)
ASIA
Patients with at least one hospitalization for PAH (n)
Total number of hospitalizations for PAH (n)
24
19
13
Total number of days of hospitalization for PAH (n)
203
146
102
20.0
14.0
9.5
13.4, 29.8
9.0, 22.0
5.5, 16.4
1.7
1.1
0.7
0.9, 2.5
0.5, 1.6
0.3, 1.2
22.1
14.5
9.9
14.7, 33.3
9.3, 22.7
5.8, 17.1
1.7
1.1
0.8
0.9, 2.4
0.5, 1.6
0.3, 1.2
N=42
N=44
N=41
Patients with at least one hospitalization for PAH (n)
17
7
11
Total number of hospitalizations for PAH (n)
20
8
12
Total number of days of hospitalization for PAH (n)
156
44
96
28.7
8.2
14.8
18.5, 44.5
4.1, 16.4
8.4, 26.0
2.2
0.5
1.2
1.1, 3.4
0.1, 0.8
0.4, 2.0
27.3
9.6
14.2
17.3, 43.1
4.8, 19.2
8.0, 25.4
UNADJUSTED ANALYSES
PAH hospitalization count (PAH hospitalization rate per
100PY; 95% CI)
PAH hospitalization days (mean annual number of PAHrelated hospital days; 95% CI)
ANALYSES ADJUSTED FOR WHO FC AT BASELINE
PAH hospitalization count (PAH hospitalization rate per
100PY; 95% CI)
PAH hospitalization days (mean annual number of PAHrelated hospital days; 95% CI)
LATIN AMERICA
UNADJUSTED ANALYSES
PAH hospitalization count (PAH hospitalization rate per
100PY; 95% CI)
PAH hospitalization days (mean annual number of PAHrelated hospital days; 95% CI)
ANALYSES ADJUSTED FOR WHO FC AT BASELINE
PAH hospitalization count (PAH hospitalization rate per
100PY; 95% CI)
PAH hospitalization days (mean annual number of PAHrelated hospital days; 95% CI)
2.3
0.5
1.1
1.2, 3.4
0.1, 0.9
0.4, 1.8
*The interpretation of exploratory subgroup analyses should be done with caution as there are limitations due to
small sample size, low number of events and the absence of statistical adjustment for multiple testing.
PY: patient-years