Download Supplementary materials to Incident and prevalent cohorts with

Supplementary materials to Incident and prevalent cohorts with
pulmonary arterial hypertension: insight from SERAPHIN
Simonneau G, Channick RN, Delcroix M, Galiè N, Ghofrani H-A, Jansa P, Le Brun F-O,
Mehta S, Perchenet L, Pulido T, Sastry BKS, Sitbon O, Souza R, Torbicki A, Rubin LJ
Table of Contents
TABLE S1. Adjusted hazard ratios for the comparison between placebo incident and
prevalent patients following adjustment for baseline geographical region, WHO FC,
mRAP and aetiology................................................................................................... 2
TABLE S2a. Summary of patient listings for all deaths up to end of study, in
treatment-naïve incident and prevalent patients in the SERAPHIN study .................. 3
TABLE S2b. Individual patient listings for all deaths up to end of study, in treatmentnaïve incident and prevalent patients in the SERAPHIN study .................................. 4
FIGURE S1. Forest plot for risk of time to event endpoints in treatment-naïve
incident and prevalent cohorts of patients with pulmonary arterial hypertension
treated with macitentan 3 mg versus placebo ............................................................ 7
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TABLE S1. Adjusted hazard ratios for the comparison between placebo incident and prevalent patients following adjustment for baseline
geographical region, WHO FC, mRAP and aetiology
Endpoints
Morbidity and mortality
Death due to PAH or
hospitalisation for PAH
All-cause mortality
Variable to adjust for
HR (95% CI)
Unadjusted
2.19 (1.24, 3.87)
Geographical region
2.21 (1.20, 4.05)
WHO FC
1.85 (1.02, 3.37)
mRAP
2.35 (1.31, 4.22)
Aetiology
2.16 (1.21, 3.86)
All*
1.96 (1.01, 3.83)
Unadjusted
2.47 (1.27, 4.83)
Geographical region
2.48 (1.19, 5.17)
WHO FC
1.82 (0.91, 3.66)
mRAP
2.48 (1.26, 4.91)
Aetiology
2.57 (1.30, 5.04)
All*
1.98 (0.89, 4.43)
Unadjusted
0.79 (0.34, 1.85)
Geographical region
0.52 (0.20, 1.35)
WHO FC
0.56 (0.23, 1.36)
mRAP
0.78 (0.33, 1.84)
Aetiology
0.89 (0.37, 2.13)
All*
0.43 (0.14, 1.28)
*Adjusted for geographical region, WHO FC, mRAP and aetiology combined; CI, confidence interval; HR, hazard ratio; mRAP, mean right atrial pressure;
WHO FC, World Health Organization Functional Class
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TABLE S2a. Summary of patient listings for all deaths up to end of study, in treatment-naïve incident and prevalent patients in the SERAPHIN
study
Age,
mean
(yr)
Time from PAH
diagnosis to
study entry,
mean±SD
(months)
Placebo (n=8)
66.1
Macitentan 3 mg (n=7)
Macitentan 10 mg (n=4)
(number)
PVR,
mean±SD
(Wood units)
Cardiac
index
2
(L/min/m )
mPAP,
mean
(mmHg)
mRAP,
mean
(mmHg)
6MWD,
mean
(m)
Time to death
from baseline,
mean±SD
(months)
1.6±1.6
0:2:6:0
11.7±8.1
2.25
49.3
6.0
321.0
5.9±6.0
60.3
2.8±1.6
0:4:3:0
11.8±4.3
2.32
54.1
8.7
367.9
11.1±8.8
45.0
2.7±1.9
0:0:4:0
11.3±5.8
2.43
55.3
8.0
246.8
9.7±7.6
Placebo (n=16)
45.6
41.1±41.6
0:6:8:2
15.2±9.5
2.10
58.8
9.1
283.4
8.9±8.6
Macitentan 3 mg (n=8)
55.0
48.1±50.0
0:1:6:1
13.4±9.6
2.41
56.4
10.3
248.1
13.0±10.7
WHO FC,
I:II:III:IV
Incident patients
Prevalent patients
Macitentan 10 mg (n=7)
44.3
34.4±18.0
0:2:4:1
19.3±9.8
2.10
68.6
13.4
297.9
18.3±15.1
6MWD, 6-minute walk distance; mPAP, mean pulmonary arterial pressure; mRAP, mean right atrial pressure; PVR, pulmonary vascular resistance;
SD, standard deviation; WHO FC, World Health Organization Functional Class
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TABLE S2b. Individual patient listings for all deaths up to end of study, in treatment-naïve incident and prevalent patients in the SERAPHIN
study
Country
Time from PAH
Cardiac
Aetiology of
PVR
mPAP
diagnosis
WHO FC
index
PAH
(Wood units)
(mmHg)
2
(months)
(L/min/m )
mRAP
(mmHg)
6MWD (m)
Cause of death
Time to death
from baseline
(months)
35
2
333
Renal insufficiency
5.4
2.27
1.58
40
50
2
1
265
370
Right heart failure
Deterioration of PAH
2.0
0.8
2.17
27
6
443
Stroke
18.3
Congestive left heart
failure leading to
cardiogenic shock
1.0
Pt. No.
Sex
Age (yr)
Germany
1
M
75
2.1
IPAH
3
6.3
2.08
Germany
Germany
2
3
F
F
69
69
0.2
0.2
CTD
IPAH
3
3
7.6
17.5
Norway
4
M
65
2.8
IPAH
2
3.2
Significant comorbidities
Incident patients
Placebo (n=8)
Thailand
5
M
51
0.5
IPAH
Israel
Mexico
US
3
23.8
1.51
59
10
294
6
F
75
5.0
IPAH
7
M
42
0.3
CHD
3
7.0
2
23.8
3.14
53
17
220
Urosepsis
0.1
2.28
100
8
344
4.9
4.1
2.94
30
2
299
Severe sepsis
Respiratory failure
secondary to
congestive heart
failure
8
F
83
1.4
CTD
3
Germany
9
M
74
0.2
IPAH
Romania
Romania
10
11
M
F
47
43
3.4
3.0
IPAH
IPAH
2
11.9
1.82
46
8
480
Sudden cardiac death
5.1
3
2
14.9
13.7
1.86
2.04
72
52
5
2
411
576
Respiratory failure
Sudden death
11.2
26.5
South Africa
12
F
65
1.1
Israel
13
F
67
4.5
IPAH
2
19.6
2.04
69
11
162
Right heart failure
5.3
CTD
3
9.0
2.20
50
15
282
Worsening of PAH
6.6
Mexico
14
F
54
4.9
CTD
2
7.5
3.72
51
3
393
PAH
21.8
US
15
F
72
2.9
IPAH
3
6.3
2.55
39
17
273
Respiratory failure
1.1
9.2
Hypertension, type 2 diabetes mellitus, hypercholesterolaemia,
chronic renal failure, coronary artery disease, chronic obstructive
pulmonary disease
Hypertension, Raynaud’s phenomenon, scleroderma
Chronic obstructive pulmonary disease, drug hypersensitivity
Hypertension, atrial fibrillation, sleep apnoea syndrome, type 2
diabetes mellitus, aortic valve incompetence
NA
Skin ulcer, hypertension, diabetes mellitus, myocardial ischaemia,
peripheral vascular disorder, renal stone removal, hyponatraemia
Dengue fever, atrial septal defect repair, measles
Hypertension, hypercholesterolaemia, oedema peripheral, Barrett's
oesophagus, diarrhoea, drug hypersensitivity, carotid artery
stenosis, appendicitis, sclerodactylia, skin ulcer, Raynaud's
phenomenon
Macitentan 3 mg (n=7)
Coronary artery disease, sarcoidosis, carotid artery stenosis,
inguinal hernia repair, transurethral prostatectomy
NA
Hypertriglyceridaemia
Hypertension, chronic obstructive pulmonary disease, right
ventricular failure
Scleroderma, Raynaud's phenomenon, oedema peripheral
Measles, pulmonary tuberculosis, typhoid fever, cutaneous lupus
erythematosus, systemic lupus erythematosus, hypertension,
bronchial hyperreactivity
Chronic obstructive pulmonary disease, renal artery stent
placement, cholecystectomy, carotid endarterectomy, sleep
apnoea syndrome, oedema peripheral, hypercholesterolaemia,
hypoxia, coronary artery bypass, cerebrovascular accident, cardiac
pacemaker insertion, diabetes mellitus
Macitentan 10 mg (n=4)
Liver disorder, pulmonary embolism, diabetes mellitus,
cholelithiasis, obesity, renal failure chronic, hypothyroidism,
ascites, hypertension, arteriosclerosis coronary artery, right
ventricular failure
Germany
16
F
52
3.5
IPAH
3
8.4
2.23
52
17
270
Acute right heart
failure
2.5
Belarus
17
F
22
1.4
IPAH
3
12.1
1.58
43
10
195
Right heart ventricle
failure
18.2
Hypothyroidism, atrial septal defect, cor pulmonale
Israel
18
F
75
5.4
IPAH
3
4.5
3.44
31
3
251
Sudden death
16.4
Cholecystectomy, osteoporosis, hyperlipidaemia, oedema
peripheral, pulmonary embolism, pulmonary embolism,
hypertension, obesity, sleep apnoea syndrome, myocardial
ischaemia, coronary artery dilatation
Mexico
19
F
31
0.4
CTD
3
20.3
2.46
95
2
271
Right heart failure
leading to cardiogenic
shock
1.8
Scleroderma, Sjögren’s syndrome, systemic lupus erythematosus,
systemic arterial hypertension
4/7
Country
Time from PAH
Cardiac
Aetiology of
PVR
mPAP
diagnosis
index
WHO FC
PAH
(Wood units)
(mmHg)
(months)
(L/min/m2)
mRAP
(mmHg)
6MWD (m)
53
9
87
2.38
52
2
352
6.4
1.36
30
19
380
3
42.4
1.36
98
3
360
IPAH
3
20.5
1.46
50
2
109
IPAH
3
9.2
2.48
56
14
260
Pt. No.
Sex
Age (yr)
Germany
20
F
84
12.3
CTD
4
23.3
1.23
Belarus
21
F
39
52.0
IPAH
2
12.1
Belarus
22
M
42
131.6
IPAH
3
Belarus
23
F
16
151.6
CHD
Bulgaria
24
F
45
9.6
Romania
25
M
64
22.6
Cause of death
Time to death
from baseline
(months)
Significant comorbidities
Prevalent patients
Placebo (n=16)
Russia
26
Russia
Russia
Russia
Serbia
Ukraine
F
67
46.3
CHD
3
3.3
3.00
27
F
41
15.1
CHD
3
20.7
2.62
28
M
73
16.5
CTD
2
4.0
2.44
29
F
24
12.6
IPAH
2
16.1
2.50
70
30
31
F
M
48
33
7.9
55.0
CTD
IPAH
3
2
12.5
16.7
1.97
1.73
29
Tricuspid valve incompetence
1.9
Pancreatitis chronic hypertension, tachycardia
9.1
3.0
15.1
Ventricular septal defect repair, measles, varicella, supraventricular
tachycardia, tricuspid valve incompetence, hypoxia, right
ventricular failure
Right ventricular failure
Coronary artery disease, coronary artery bypass, dyslipidaemia
Rheumatic heart disease, atrial fibrillation, right ventricular failure,
hypertension, type 2 diabetes mellitus, cerebral ischaemia,
pyelonephritis, chronic renal failure, chronic cholecystitis, chronic
cholelithiasis, mitral valve repair
Patent ductus arteriosus repair
Myocardial ischaemia, myocardial infarction, myocardial fibrosis,
hypertension, left ventricular failure, cerebral ischaemia, gastric
ulcer
PAH progression
3.8
170
Acute heart failure (left
side)
1.9
430
Pulmonary edema,
brain edema
6.2
NA
0
5
8
15
Acute respiratory failure
Haemorrhage of upper
digestive tract
12.9
379
96
28
74
Right pulmonary artery
thromboembolism
Crest syndrome, hypertension, tricuspid valve incompetence,
pericardial effusion, renal failure, atrial septal defect,
hypercholesterolaemia,
24.1
300
17
Cardio-pulmonary
failure
Worsening of
pulmonary arterial
hypertension leading to
acute cardiopulmonary
failure
2.4
Bulk mass of head of
pancreas
12
60
Right ventricular failure
363
SLE complications
24.1
Systemic lupus erythematosus, lupus nephritis, pericarditis,
myasthenia gravis, thymectomy, osteosclerosis, hypertension, right
ventricular failure,
324
Closed skull fracture of
basis and calvarium
with brain contusion
and development of
epidural, subdural and
subarahnoid
haemorrhage
4.1
Pneumonia, blood bilirubin increased, asthenia, depression, chest
pain, head injury, appendicectomy, cholecystitis chronic, myopia,
cor pulmonale, right ventricular failure, venous thrombosis,
neurological infection, CSFpressure increased, convulsion, upper
respiratory tract infection, right ventricular failure
Ukraine
32
M
26
44.6
CHD
2
12.4
2.52
75
8
392
Acute coronary death
26.5
China
South Africa
33
34
F
F
15
34
50.9
20.1
CHD
HIV
2
3
24.1
13.6
1.65
2.09
67
57
12
18
258
295
Worsening of PAH
Renal failure
1.7
4.5
Israel
35
M
79
8.1
IPAH
4
6.4
3.14
46
2
76
Septic shock
0.9
Ventricular septal defect repair, lobar pneumonia,
tracheobronchitis, iron deficiency anaemia, bronchitis, ear infection,
chronic tonsillitis, adenoiditis, pharyngitis, bronchitis, acute
sinusitis, otitis media acute, bronchitis chronic pericarditis, post
procedural complication, aortic valve incompetence, right
ventricular failure, atrial septal defect, blood bilirubin increased
Ventricular septal defect, ventricular septal defect repair
Hypothyroidism, pleural effusion, right ventricular failure
Coronary artery disease, myocardial infarction, coronary artery
bypass, renal failure chronic, polycythaemia vera
Macitentan 3 mg (n=8)
Russia
36
F
53
88.7
IPAH
4
26.3
1.42
78
14
80
Russia
37
F
38
9.5
IPAH
3
29.5
1.21
68
13
317
Serbia
38
F
61
162.3
CHD
3
5.4
2.29
36
10
172
China
39
F
41
12.9
CTD
3
NA
3.15
69
3
462
5/7
PAH worsening
Chronic cardiac and
respiratory failure
Non ST-segment
elevation myocardial
infarction
Right heart failure
37.4
Autoimmune thyroiditis, tricuspid valve incompetence
5.9
Tricuspid valve incompetence, Raynaud's phenomenon
8.8
Hypertension, atrial fibrillation, type 2 diabetes mellitus, right
ventricular failure, atrial septal defect
4.1
Mixed connective tissue disease
Country
India
Pt. No.
Sex
Age (yr)
40
M
23
Time from PAH
Cardiac
Aetiology of
PVR
mPAP
diagnosis
index
WHO FC
PAH
(Wood units)
(mmHg)
(months)
(L/min/m2)
49.3
IPAH
2
7.7
3.52
51
mRAP
(mmHg)
6MWD (m)
6
390
Cause of death
Worsening of right
heart failure
Metabolic acidosis
secondary to GI bleed
Right heart failure
due to abdominal
carcinomatosis
Time to death
from baseline
(months)
Significant comorbidities
9.4
NA
18.9
Dyslipidaemia, hypertension, hyponatraemia, B-cell lymphoma,
Raynaud's phenomenon, right ventricular failure
17.2
Hypertension, intermittent claudication, aortic bypass, atrial
fibrillation, renal cell carcinoma
Scleroderma, cholecystectomy, hypertension, peripheral arterial
occlusive disease, Raynaud's phenomenon, squamous cell
carcinoma of skin, right ventricular failure
Israel
41
F
79
7.5
IPAH
3
13.0
2.72
75
14
222
Argentina
42
M
75
34.6
IPAH
3
3.8
2.84
34
6
216
Argentina
43
F
70
20.2
CTD
3
8.0
2.11
40
16
126
Cardiac arrest
2.3
Macitentan 10 mg (n=7)
Croatia
44
M
74
64.5
CHD
2
3.3
2.63
29
20
268
Cardio-respiratory
arrest
17.3
Russia
45
F
35
41.4
IPAH
3
28.4
2.39
109
3
369
Pulmonary embolism
35.2
Serbia
46
M
60
48.8
IPAH
3
16.1
1.71
62
12
297
Sudden death
39.7
Serbia
47
F
47
7.5
CTD
4
25.1
1.43
70
17
162
Ukraine
48
F
58
37.0
IPAH
3
14.6
2.30
72
15
249
China
49
M
17
18.3
CHD
3
13.1
2.38
51
13
423
China
50
F
19
23.1
IPAH
2
34.4
1.55
87
14
317
Congestive right heart
failure
Worsening of right
heart failure, left heart
failure, cardiovascular
collapse
Arrhythmia
Decompensated right
heart failure due to
IPAH
2.9
Tibia fracture, inguinal hernia repair, atrial fibrillation, atrial septal
defect, atrial septal defect repair, gastric antral vascular ectasia
Pneumonia, bronchitis, hypertension, polycythaemia, goitre,
haemoglobin increased, haematocrit increased, right ventricular
failure, hepatomegaly, oedema peripheral
Pericarditis, angina pectoris, hypertension, iliac artery stenosis, ,
diabetes mellitus
Scleroderma, hypertension
0.9
Cholecystitis chronic, biliary dyskinesia, cor pulmonale chronic,
right ventricular failure, drug hypersensitivity, hypotension, angina
pectoris, hepatic enzyme increased, gastroduodenitis, venous
insufficiency, pyelonephritis chronic, encephalopathy
Ventricular septal defect repair
28.2
Oedema peripheral, right ventricular hypertrophy
4.1
6MWD, 6-minute walk distance; CHD, congenital heart disease; CTD, connective tissue disease; GI, gastrointestinal; HIV, human immunodeficiency virus;
IPAH, idiopathic pulmonary arterial hypertension; mPAP, mean pulmonary arterial pressure; mRAP, mean right atrial pressure; NA, not available; PAH,
pulmonary arterial hypertension; Pt. No., patient number; PVR, pulmonary ventricular rate; WHO FC, World Health Organization Functional Class
6/7
FIGURE S1. Forest plot for risk of time to event endpoints in treatment-naïve incident and
prevalent cohorts of patients with pulmonary arterial hypertension treated with macitentan 3
mg versus placebo
CI, confidence interval; EOS, end of study; EOT, end of treatment; PAH, pulmonary arterial
hypertension
7/7