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Kozu et al., Page 1
Online data supplement.
Current status of long-term prognosis among all subtypes of pulmonary hypertension in Japan
Katsuya Kozu, Koichiro Sugimura, Masaaki Ito, Ken-ichi Hirata, Koichi Node,
Takuya Miyamoto, Shuichi Ueno, Hiroshi Watanabe,
Hiroaki Shimokawa; for the Japanese Pulmonary Circulation Study Group
Table of contents
Supplementary Table S1. Baseline patient characteristics of PAH and PVOD.............................................Page 2
Supplementary Table S2. Baseline patient characteristics of PAH by maximum medication reached during
follow-up..........................................................................................................................................................Page 4
Supplementary Table S3. Cox proportional hazards models of baseline variables in PAH..........................Page 6
Supplementary Table S4. Cox proportional hazards models of eGFR in PAH.............................................Page 7
Supplementary Table S5. Cox proportional hazards models of BNP in PAH with or without parenteral
prostacyclin analogue.......................................................................................................................................Page 8
Supplementary Table S6. Cox proportional hazards models including the number of PH-specific drugs in PAH
adjusted for the independent prognostic factors...............................................................................................Page 9
Supplementary Table S7. Baseline patient characteristics of PH-LHD......................................................Page 10
Supplementary Table S8. Cox proportional hazards models of baseline variables in PH-LHD.................Page 11
Supplementary Table S9. Cox proportional hazards models of baseline variables in CTEPH...................Page 12
Supplementary Table S10. Cox proportional hazards models of BPA in CTEPH......................................Page 13
Supplementary Table S11. Comparison of the prognosis of patients with PAH between the Japanese registry and
other recent registries...............................................................................................................................Page 14
Supplementary Table S12. Comparison of the prognosis of patients with CTEPH between the Japanese registry
and other recent registries...............................................................................................................................Page 17
Supplementary Fig. S1. Study flow chart....................................................................................................Page 19
Supplementary Fig. S2. Long-term prognosis of patients with pulmonary hypertension in terms of incident vs.
prevalent cases................................................................................................................................................Page 20
Supplementary Fig. S3. Long-term prognosis of PAH patients with CTD vs. IPAH, PAH patients with CTD by
disease subtypes, and patients with CTEPH by BMI.....................................................................................Page 21
Supplementary material. The Japanese Pulmonary Circulation Study Group Investigators.......................Page 22
Kozu et al., Page 2
Supplementary Table S1. Baseline patient characteristics of PAH and PVOD
IPAH/HPAH SSc Non-SSc CTD Portal HT CHD PVOD
N 98 (31) 56 (18) 75 (24) 26 (8) 54 (17) 5 (2)
Male 29 (30) 9 (16) 8 (11) 9 (35) 18 (33) 2 (40)
Age, years 42±20 64±12†‡§‖ 50±15 45±17 49±18 45±17
BMI, kg/m2 21.2±3.9 20.8±3.7 20.3±3.5 23.2±5.3 20.4±3.6 20.6±3.0
WHO FC I* 7 (7) 1 (2) 8 (11) 3 (12) 8 (15) 0
II 39 (41) 15 (27) 29 (41) 15 (60) 19 (36) 1 (20)
III 41 (43) 34 (62) 28 (39) 5 (20) 22 (42) 1 (20)
IV 8 (8) 5 (9) 6 (8) 2 (8) 4 (8) 3 (60)
6MWD, m 357±139 298±132†‡§ 367±116 404±129 329±113 258±60
BNP, pg/ml 140 (47-339) 89 (42-384) 97 (34-255) 29 (21-130)‖ 136 (39-285) 38 (29-472)
eGFR,
ml/min/1.73m272±30‡ 67±26‡ 89±33‖ 85±28 69±26 65±17
LVEF, % 71±12 67±8 70±10 73±10 67±13 72±6
FVC,
% predicted91±17‖ 76±21†§ 85±21‖ 91±12‖ 71±20 110±17
FEV1,
% predicted89±18 83±24 88±18 82±21 77±22 92±18
DLCO,
% predicted64±22‖ 41±19†‡§‖ 59±27‖ 58±13‖ 81±16 47±5
mPAP, ,mmHg 53±17‡§ 35±8†§‖ 38±10‖ 42±12 55±21 46±17
PAWP, mmHg 9±4 9±5 9±5 10±6 10±5 6±2
RAP, mmHg 7±5 6±4 6±4 5±3 7±4 5±2
CI, L/min/m2 2.6±0.9‡§ 3.0±0.9† 3.2±0.8 3.4±0.9 3.0±1.2 2.6±1.0
PVR,
Wood units11.6 (7.9-16.1)‡§ 5.8 (3.8-9.3)†‖ 6.1 (4.1-8.9)‖ 5.7 (3.8-8.4) 9.4 (4.7-16.0) 10.7 (5.5-17.7)
SvO2, % 66±9§ 69±7 69±7 72±10 70±12 69±7
PAC,
mL/mmHg1.3±0.8‡§ 1.9±0.8†‖ 2.0±1.0‖ 2.4±1.2‖ 1.3±0.8 1.7±1.4
Kozu et al., Page 3
Data are presented as n (%), mean±SD or median (interquartile range), unless otherwise stated. Percentages in
this column may not add up exactly 100% because of rounding. BMI, body-mass index; BNP, brain natriuretic
peptide; CHD, congenital heart disease; CI, cardiac index; CTD, connective tissue disease; DLCO, diffusing
capacity of the lung for carbon monoxide; eGFR, estimated glomerular filtration rate; FEV1, forced expiratory
volume in one second; FVC, forced vital capacity; HPAH, heritable pulmonary arterial hypertension; HT,
hypertension; IPAH, idiopathic pulmonary arterial hypertension; LVEF, left ventricular ejection fraction;
mPAP, mean pulmonary arterial pressure; PAC, pulmonary arterial capacitance; PAH, pulmonary arterial
hypertension; PAWP, pulmonary artery wedge pressure; PVOD, pulmonary veno-occlusive disease; PVR,
pulmonary vascular resistance; RAP, right atrial pressure; SSc, systemic sclerosis; SvO2, mixed venous oxygen
saturation; WHO FC, World Health Organization functional class; 6MWD, 6-minute walk distance. *Percentage of the cases in which the data were obtained. †P<0.01 in comparison to IPAH/HPAH; ‡P<0.01 in
comparison to non-SSc CTD; §P<0.01 in comparison to Portal HT; ‖P<0.01 in comparison to CHD.
Kozu et al., Page 4
Supplementary Table S2. Baseline patient characteristics of PAH by maximum medication reached
during follow-up
Monotherapy Double combination therapy
Triple combination therapy
N 55 101 131Follow-up duration, years 5.0±3.8 4.9±3.3 5.6±4.3
PAH subgroup
IPAH/HPAH 14 (25) 26 (26) 55 (42)
Drug- and toxin-induced 1 (2) 0 0
CTD 24 (44) 54 (53) 43 (33)
Portal HT 6 (11) 11 (11) 8 (6)
CHD 10 (18) 10 (10) 24 (18)
CTD + CHD 0 0 1 (1)
Male 14 (25) 19 (19) 32 (24)
Age, years 55±18‡ 51±17‡ 45±20
BMI, kg/m2 21±4 21±4 21±4
WHO FC I* 5 (9) 8 (8) 9 (7)
II 20 (38) 31 (33) 53 (41)
III 24 (45) 45 (47) 59 (45)
IV 4 (8) 11 (12) 9 (7)
6MWD, m 305±146 350±144 357±119
BNP, pg/ml 169 (38-368) 93 (32-236) 97 (35-308)
eGFR, ml/min/1.73m2 80±38 75±26 81±54
FVC, % predicted 79±23 84±20 85±20
FEV1, % predicted 83±24 88±20§ 81±20
DLCO, % predicted 59±26 54±25 60±23
mPAP, mmHg 41±17‡ 43±14‡ 51±18
PAWP, mmHg 9±5 9±5 9±5
RAP, mmHg 6±4 6±4 6±4
CI, L/min/m2 3.1±1.0 2.9±0.9 2.8±1.2
PVR, Wood units 6.3 (4.0-10.4)‡ 7.5 (4.8-11.4)‡ 10.4 (6.0-14.0)
SvO2, % 70±9 68±10 67±8.4
PAC, mL/mmHg 1.8±1.1§ 1.8±0.9‡ 1.4±0.9
Kozu et al., Page 5
Supplementary Table S2. (Continued)
Monotherapy Double combination therapy
Triple combination therapy
PH-specific medication Prostacyclin analogue 22 (40) 50 (50) 131 (100)
Parenteral prostacyclin analogue 6 (11)‡ 14 (14)‡ 45 (34)
Beraprost 16 (29)‡ 36 (36)‡ 86 (66)
Endothelin receptor antagonist 17 (31)†‡ 79 (78)‡ 131 (100)
PDE-5 inhibitor or sGC stimulator 16 (29)†‡ 73 (72)‡ 131 (100)
Calcium channel blocker 12 (22) 25 (25) 20 (15)
Loop diuretics 25 (45) 42 (42) 66 (50)
Mineralocorticoid receptor antagonist 18 (33) 31 (31) 41 (31)
Tolvaptan 2 (4) 5 (5) 7 (5)
Anticoagulants 20 (36) 40 (40) 47 (36)
Data are presented as n (%), mean±SD or median (interquartile range), unless otherwise stated. Percentages
in this column may not add up exactly 100% because of rounding. BMI, body-mass index; BNP, brain
natriuretic peptide; CHD, congenital heart disease; CI, cardiac index; CTD, connective tissue disease;
DLCO, diffusing capacity of the lung for carbon monoxide; eGFR, estimated glomerular filtration rate;
FEV1, forced expiratory volume in one second; FVC, forced vital capacity; HPAH, heritable pulmonary
arterial hypertension; HT, hypertension; IPAH, idiopathic pulmonary arterial hypertension; LVEF, left
ventricular ejection fraction; mPAP, mean pulmonary arterial pressure; PAC, pulmonary arterial capacitance;
PAH, pulmonary arterial hypertension; PAWP, pulmonary artery wedge pressure; PDE-5, phosphodiesterase
type-5; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RAP, right atrial pressure; sGC,
soluble guanylate cyclase; SvO2, mixed venous oxygen saturation; WHO FC, World Health Organization
functional class; 6MWD, 6-minute walk distance. *Percentage of the cases in which the data were obtained. †P<0.01 in comparison to double combination therapy; ‡P<0.01 in comparison to triple combination therapy; §P<0.05 in comparison to triple combination therapy.
Kozu et al., Page 6
Supplementary Table S3. Cox proportional hazards models of baseline variables in PAH
Univariable Multivariable
HR (95% CI) P value HR (95% CI) P value
Male 1.75 (1.10-2.72) 0.02 2.33 (1.35-3.94) 0.003
Age <30, years 1.49 (0.77-2.83) 0.23 1.15 (0.51-2.54) 0.72
30≤ Age <45, years Reference Reference
45≤ Age <60, years 1.29 (0.68-2.42) 0.44 1.45 (0.67-3.14) 0.34
60≤ Age <75, years 1.60 (0.86-2.99) 0.14 1.53 (0.69-3.40) 0.29
Age ≥75, years 3.47 (1.63-7.08) 0.002 4.99 (2.11-11.6) 0.0004
BMI <18.5, kg/m2 2.00 (1.26-3.17) 0.004 2.26 (1.28-3.96) 0.005
18.5≤ BMI <25, kg/m2 Reference Reference
BMI ≥25, kg/m2 1.41 (0.75-2.49) 0.27 1.87 (0.92-3.64) 0.08
WHO FC III/IV 2.34 (1.51-3.73) 0.0001 1.90 (1.14-3.24) 0.01
BNP, per 100 pg/ml 1.04 (0.98-1.09) 0.16
eGFR, ml/min/1.73m2 0.99 (0.98-1.00) 0.01
mPAP, mmHg 1.01 (1.00-1.02) 0.14
PAWP, mmHg 1.01 (0.96-1.05) 0.67
RAP, mmHg 1.05 (1.00-1.10) 0.07
CI, L/min/m2 0.92 (0.73-1.12) 0.44
PVR, Wood units 1.02 (0.99-1.04) 0.18
SvO2, % 0.97 (0.94-0.99) 0.02 0.96 (0.94-0.99) 0.005
PAC, mL/mmHg 0.79 (0.61-1.00) 0.054
BMI, body-mass index; BNP, brain natriuretic peptide; CI, cardiac index; DPG, diastolic pressure gradient;
eGFR, estimated glomerular filtration rate; mPAP, mean pulmonary arterial pressure; PAC, pulmonary
arterial capacitance; PAH, pulmonary arterial hypertension; PAWP, pulmonary artery wedge pressure; PH,
pulmonary hypertension; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SvO2, mixed
venous oxygen saturation; WHO FC, World Health Organization functional class.
Kozu et al., Page 7
Supplementary Table S4. Cox proportional hazards models of eGFR in PAH
Cox proportional hazards models HR (95% CI) P value
Unadjusted 0.990 (0.981-0.998) 0.01
Adjusted for age group, BMI group, WHO FC 0.987 (0.977-0.997) 0.008
Adjusted for age group, BMI group, WHO FC, sex 0.990 (0.978-1.000) 0.06
Adjusted for age group, BMI group, WHO FC, sex, SvO2 0.995 (0.981-1.009) 0.48
BMI, body-mass index; eGFR, estimated glomerular filtration rate; PAH, pulmonary arterial hypertension;
SvO2, mixed venous oxygen saturation; WHO FC, World Health Organization functional class.
Kozu et al., Page 8
Supplementary Table S5. Cox proportional hazards models of BNP in PAH with or without
parenteral prostacyclin analogue
With parenteral prostacyclin analogue Without parenteral prostacyclin analogueP value for
interaction
HR (95% CI) P value HR (95% CI) P value
BNP, per 100 pg/mL 0.99 (0.75-1.19) 0.89 1.08 (0.98-1.17) 0.10 0.05
Multivariable analysis was performed adjusted for sex, age group, body-mass index group, World Health Organization
functional class, and mixed venous oxygen saturation. BNP, brain natriuretic peptide; PAH, pulmonary arterial
hypertension.
Kozu et al., Page 9
Supplementary Table S6. Cox proportional hazards models including the number of
PH-specific drugs in PAH adjusted for the independent prognostic factors
Univariable Multivariable
HR (95% CI) P value HR (95% CI) P value
With parenteral prostacyclin analogue
Monotherapy Reference Reference
Double combination therapy 1.11 (0.35-4.22) 0.86 0.19 (0.02-1.34) 0.09
Triple combination therapy 0.65 (0.23-2.30) 0.46 0.20 (0.03-1.05) 0.06
Without parenteral prostacyclin analogue
No PH-specific drugs or monotherapy Reference Reference
Double combination therapy 0.92 (0.52-1.65) 0.78 0.94 (0.50-1.78) 0.85
Triple combination therapy 0.47 (0.24-0.90) 0.02 0.48 (0.24-0.94) 0.03
Multivariable analysis was performed adjusted for sex, age group, body-mass index group, and World Health
Organization functional class. PAH, pulmonary arterial hypertension; PH, pulmonary hypertension.
Kozu et al., Page 10
Supplementary Table S7. Baseline patient characteristics of PH-LHD
Systolic Diastolic Valvular
N 161 (38) 89 (21) 175 (41)Male 132 (82)†‡ 53 (60) 84 (48)
Age, years 58±16†‡ 65±13 67±11
BMI, kg/m2 24.3±6.0‡ 24.1±4.1‡ 22.7±3.9
WHO FC I* 11 (8) 13 (18) 21 (14)
II 58 (41) 30 (42) 74 (50)
III 49 (35) 24 (34) 41 (28)
IV 24 (17) 4 (6) 12 (8)
6MWD, m 351±156 302±33 350±68
BNP, pg/ml 685 (348-1156)†‡ 318 (153-587) 306 (135-841)
eGFR, ml/min/1.73m2 44±21 47±23 46±23
LVEF, % 32±13†‡ 65±13‡ 60±15
FVC, % predicted 80±20 81±17 85±19
FEV1, % predicted 103±17 109±18‡ 98±18
DLCO, % predicted 78±28 80±27 89±27
mPAP, mmHg 34±7† 30±5‡ 34±8
PAWP, mmHg 23±6† 20±4‡ 23±6
DPG, mmHg 1 (-2-4)‡ 0 (-2-2) -1 (-3-2)
RAP, mmHg 10±6 11±5‡ 10±5
CI, L/min/m2 2.4±0.6†‡ 2.8±0.9 2.7±0.8
PVR, Wood units 2.4 (1.6-3.4) 2.1 (1.6-3.2) 2.3 (1.6-3.4)
SvO2, % 63±9† 67±8 65±8
PAC, mL/mmHg 2.4±1.4† 3.0±1.4‡ 2.3±1.0Data are presented as n (%), mean±SD or median (interquartile range), unless otherwise stated.
Percentages in this column may not add up exactly 100% because of rounding. BMI, body-mass index;
BNP, brain natriuretic peptide; CI, cardiac index; DLCO, diffusing capacity of the lung for carbon
monoxide; DPG, diastolic pulmonary vascular pressure gradient; eGFR, estimated glomerular filtration
rate; FEV1, forced expiratory volume in one second; FVC, forced vital capacity; LVEF, left ventricular
ejection fraction; mPAP, mean pulmonary arterial pressure; PAC, pulmonary arterial capacitance; PAWP,
pulmonary artery wedge pressure; PH-LHD, pulmonary hypertension associated with left-heart disease;
PVR, pulmonary vascular resistance; RAP, right atrial pressure; SvO2, mixed venous oxygen saturation;
WHO FC, World Health Organization functional class; 6MWD, 6-minute walk distance. *Percentage of the
cases in which the data were obtained. †P<0.05 vs. LHD-diastolic; ‡P<0.05 vs. LHD-valvular.
Kozu et al., Page 11
Supplementary Table S8. Cox proportional hazards models of baseline variables in
PH-LHD
Univariable Multivariable
HR (95% CI) P value HR (95% CI) P value
Male 1.01 (0.72-1.45) 0.94
Age <30, years 0.70 (0.04-4.43) 0.74 1.46 (0.07-9.97) 0.75
30≤ Age <45, years Reference Reference
45≤ Age <60, years 2.73 (1.16-8.05) 0.02 2.38 (0.91-8.18) 0.08
60≤ Age <75, years 3.06 (1.32-8.94) 0.007 2.52 (1.00-8.49) 0.051
Age ≥75, years 4.91 (2.04-14.7) 0.0001 3.07 (1.14-10.7) 0.03
BMI <18.5, kg/m2 1.30 (0.74-2.13) 0.35
18.5≤ BMI <25, kg/m2 Reference
BMI ≥25, kg/m2 0.89 (0.60-1.30) 0.55
WHO FC III/IV 2.20 (1.53-3.18) <0.0001 2.06 (1.39-3.08) 0.0003
BNP, per 100 pg/ml 1.03 (1.02-1.05) 0.0001 1.02 (1.00-1.04) 0.051
eGFR, ml/min/1.73m2 0.98 (0.97-0.99) <0.0001 0.99 (0.98-1.00) 0.04
mPAP, mmHg 1.01 (0.98-1.03) 0.50
PAWP, mmHg 1.02 (0.99-1.05) 0.22
DPG, mmHg 1.00 (0.97-1.04) 0.93
RAP, mmHg 1.02 (0.99-1.05) 0.24
CI, L/min/m2 0.94 (0.73-1.19) 0.59
PVR, Wood units 1.01 (0.92-1.09) 0.90
SvO2, % 0.95 (0.93-0.97) <0.0001
PAC, mL/mmHg 0.78 (0.65-0.93) 0.005
BMI, body-mass index; BNP, brain natriuretic peptide; CI, cardiac index; DPG, diastolic pressure gradient;
eGFR, estimated glomerular filtration rate; mPAP, mean pulmonary arterial pressure; PAC, pulmonary arterial
capacitance; PAWP, pulmonary artery wedge pressure; PH, pulmonary hypertension; PH-LHD, pulmonary
hypertension associated with left-heart disease; PVR, pulmonary vascular resistance; RAP, right atrial
pressure; SvO2, mixed venous oxygen saturation; WHO FC, World Health Organization functional class.
Kozu et al., Page 12
Supplementary Table S9. Cox proportional hazards models of baseline variables in CTEPH
Univariable Multivariable
HR (95% CI) P value HR (95% CI) P value
Male 2.03 (0.68-5.56) 0.19
Age, years 1.038 (0.997-1.088) 0.07 1.042 (1.000-1.095) 0.051
BMI <18.5, kg/m2 1.86 (0.10-10.4) 0.59 1.47 (0.08-8.34) 0.73
18.5≤ BMI <25, kg/m2 Reference Reference
BMI ≥25, kg/m2 2.70 (0.94-7.61) 0.06 3.00 (1.04-8.50) 0.04
WHO FC III/IV 1.88 (0.58-7.18) 0.30
BNP, per 100 pg/ml 1.15 (1.02-1.28) 0.02
eGFR, ml/min/1.73m2 0.93 (0.88-0.97) 0.001
mPAP, mmHg 1.01 (0.96-1.05) 0.73
PAWP, mmHg 1.097 (0.999-1.184) 0.05
RAP, mmHg 1.11 (1.03-1.18) 0.01
CI, L/min/m2 0.78 (0.35-1.53) 0.50
PVR, Wood units 1.07 (0.96-1.17) 0.21
SvO2, % 0.93 (0.87-0.99) 0.03
PAC, mL/mmHg 0.82 (0.32-1.83) 0.65
BMI, body-mass index; BNP, brain natriuretic peptide; CI, cardiac index; CTEPH, chronic
thromboembolic pulmonary hypertension; eGFR, estimated glomerular filtration rate; mPAP, mean
pulmonary arterial pressure; PAC, pulmonary arterial capacitance; PAWP, pulmonary artery wedge
pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SvO2, mixed venous
oxygen saturation; WHO FC, World Health Organization functional class.
Kozu et al., Page 13
Supplementary Table S10. Cox proportional hazards models of BPA in CTEPH
Cox proportional hazards models HR (95% CI) P value
Including patients underwent PEA
Unadjusted 0.17 (0.05-0.50) 0.0009
Adjusted for age 0.18 (0.05-0.51) 0.001
Adjusted for BMI group 0.19 (0.05-0.56) 0.002
Adjusted for PVR 0.18 (0.05-0.51) 0.001
Adjusted for with or without PEA 0.15 (0.04-0.45) 0.0005
Excluding patients underwent PEA
Unadjusted 0.17 (0.05-0.54) 0.003
Adjusted for age 0.20 (0.05-0.63) 0.006
Adjusted for BMI group 0.19 (0.05-0.62) 0.006
Adjusted for PVR 0.18 (0.05-0.57) 0.003
BMI, body-mass index; BPA, balloon pulmonary angioplasty; CTEPH, chronic thromboembolic pulmonary
hypertension; PEA, pulmonary endarterectomy; PVR, pulmonary vascular resistance.
Kozu et al., Page 14
Supplementary Table S11. Comparison of the prognosis of patients with PAH between the Japanese registry and other recent registries
Japanese Swiss[5] Giessen[6] ASPIRE[4] REVEAL[11] REHAP[14] French[12,13]
Study patientsIncident and
prevalent
Incident and
prevalent
Incident and
prevalentIncident Incident Prevalent
Incident and
prevalent
Incident and
prevalent
Recruitment period, years 2012-2016 1998-2012 1993-2011 2001-2010 2006-2009 1998-2008 2002-2003
No. of Patients 311 549 685 598 710 2039 866 674
PAH subgroup, %
IPAH/HPAH 32 60 43 29 50 50 36 43
Drug- and toxin-induced <1 2 NA NA 5 6 4 10
CTD 42* 18 21 31 31 24 18 15
HIV 0 7 4 1 2 2 6 6
Portal HT 8 5 7 4 6 5 7 10
CHD 17 8 13 33 6 12 18 11
Male, % 23 40 35 30 22 21 29 35
Age, years 49 57 51 54 53 52 45 50
WHO FC III/IV, % 52 74 81 78 74 53 69 75
mPAP, mmHg 45 48 51 48 50 51 54 55
PAWP, mmHg 9 12 8 9 9 9 NA 8
Kozu et al., Page 15
Supplementary Table S11. (Continued)
Japanese Swiss[5] Giessen[6] ASPIRE[4] REVEAL[11] REHAP[14] French[12,13]
RAP, mmHg 6 9 8 10 10 9 9 8
CI, L/min/m2 3.0 2.5 2.3 2.7 2.2 2.3 2.6 2.5
PVR, Wood units 7.9 9.4 10.6† 9.8 11 12 12 NA
SvO2, % 68 63 61 63 NA NA NA 63
Maximal PAH-targeted therapy, %
Monotherapy 18 46 72‡ 59 NA NA NA NA
Combination therapy 74 43 17‡ 28 NA 46§ NA NA
Double combination therapy 32 29 15‡ NA NA NA NA NA
Triple combination therapy 42 14 2‡ NA NA NA NA NA
Survival, %
1 year 91.9 87 88.2 88 86.3 90.4 87 87
3 years 82.2 69 72.2 68 69.3 76.2 75 67
5 years 74.0 NA 59.4 NA 61.2 65.4 65 NA
Kozu et al., Page 16
Data are presented as mean, unless otherwise stated. ASPIRE, Assessing the Spectrum of Pulmonary
Hypertension Identified at a Referral Center; CHD, congenital heart disease; CI, cardiac index; CTD,
connective tissue disease; HIV, human immunodeficiency virus; HPAH, heritable pulmonary arterial
hypertension; HT, hypertension; IPAH, idiopathic pulmonary arterial hypertension; mPAP, mean pulmonary
arterial pressure; PAH, pulmonary arterial hypertension; PAWP, pulmonary artery wedge pressure; PVR,
pulmonary vascular resistance; RAP, right atrial pressure; REHAP, Spanish Registry of Pulmonary Arterial
Hypertension; REVEAL, Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension
Disease Management; SvO2, mixed venous oxygen saturation; WHO FC, World Health Organization
functional class.*Including one patient with CHD. †Data expressed as median. ‡Initial therapy.§At enrollment. This data was obtained from REVEAL registry reported by Benza et al. in 2010 [10].
Kozu et al., Page 17
Supplementary Table S12. Comparison of the prognosis of patients with CTEPH between the Japanese registry and other recent registries
Japanese Swiss[5] Giessen[6] ASPIRE[4] REHAP[15]International
registry[16]
Intervention PEA Non-PEA Overall Non-PEA PEA Non-PEA Overall PEA PEA Non-PEA PEA Non-PEA
Recruitment period,
years2012-2016 1998-2012 1993-2011 2001-2010 2006-2013 2007-2009
No. of Patients 28 155 249 215 123 336 242 108 122 269 404 275
Male, % 25 23 48 NA 49 41 46 56 56 36 55 43
Age, years 55 64 63 NA 58 63 61 57 50* 69* 60* 67*
WHO FC III/IV, % 75 54 NA 82 87 87 86 72 71 81 82
mPAP, mmHg 47 42 45 NA 49 40 48 49 48 45 48* 45*
PAWP, mmHg 10 9 12 NA 8 9 11 10 NA NA 10* 10*
RAP, mmHg 8 6 9 NA 10 7 11 10 NA NA 9* 8*
CI, L/min/m2 2.3 2.7 2.3 NA 2.0 2.3 2.5 2.3 NA NA 2.2* 2.3*
PVR, Wood units 10.7 8.7 9.6 NA 10.9* 7.4* 9.2 9.8 8.6* 8.3* 9.1* 8.5*
SvO2, % 61 65 60 NA 60† 60 60 NA NA NA NA
Kozu et al., Page 18
Supplementary Table S12. (Continued)
Japanese Swiss[5] Giessen[6] ASPIRE[4] REHAP[15]International
registry[16]
Maximal PAH-
targeted therapy, %
Monotherapy 29 33 44 65 78‡ 74‡ 77 69§ NA 71 36 43
Combination Tx 46 59 43 8 8‡ 8‡ 8 NA NA 11 0 18
Double
combination Tx32 33 34 8 7‡ 7‡ NA NA NA NA 0 18
Triple combination
Tx14 26 9 <1 1‡ 1‡ NA NA NA NA 0 0
Survival, %
1 year 92.9 97.4 NA 91 96.1 84.5 89 NA 97 93 93 88
3 years 88.8 94.7 NA 77 87.1 72.5 71 83 91 81 89 70
5 years 88.8 92.4 NA NA 76.7 61.8 NA NA 86 65 NA NA
Data are presented as mean, unless otherwise stated. ASPIRE, Assessing the Spectrum of Pulmonary Hypertension Identified at a Referral Center; CHD, congenital
heart disease; CI, cardiac index; CTEPH, chronic thromboembolic pulmonary hypertension; mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial
hypertension; PAWP, pulmonary artery wedge pressure; PEA, pulmonary endarterectomy; PVR, pulmonary vascular resistance; RAP, right atrial pressure; REHAP,
Spanish Registry of Pulmonary Arterial Hypertension; SvO2, mixed venous oxygen saturation; Tx, therapy; WHO FC, World Health Organization functional class.*Data expressed as median. †Data from all of CTEPH patients. ‡Initial therapy. §Oral monotherapy.
Kozu et al., Page 19
Supplementary Fig. S1
Study flow chart. BPA, balloon pulmonary angioplasty; CHD, congenital heart disease; COPD,
chronic obstructive pulmonary disease; CTD, connective tissue disease; CTEPH, chronic
thromboembolic pulmonary hypertension; HPAH, heritable pulmonary arterial hypertension; HT,
hypertension; ILD, interstitial lung disease; IPAH, idiopathic pulmonary arterial hypertension; PAH,
pulmonary arterial hypertension; PEA, pulmonary endarterectomy; PH-LHD, pulmonary
hypertension associated with left-heart disease; PH-lung, pulmonary hypertension associated with
lung disease; PVOD, pulmonary veno-occlusive disease; SSc, systemic sclerosis.
Kozu et al., Page 20
Supplementary Fig. S2
Long-term prognosis of patients with pulmonary hypertension in terms of incident vs. prevalent
cases in (A) pulmonary arterial hypertension, (B) pulmonary hypertension associated with left-heart
disease, and (C) chronic thromboembolic pulmonary hypertension.
Kozu et al., Page 21
Supplementary Fig. S3
Long-term prognosis of (A) pulmonary arterial hypertension (PAH) patients with connective tissue
disease (CTD) vs. idiopathic pulmonary arterial hypertension (IPAH), (B) PAH patients with CTD
by disease subtypes, and (C) patients with chronic thromboembolic pulmonary hypertension by
body-mass index (BMI).
MCTD, mixed connective tissue disease; SjS, sjögren's syndrome; SLE, systemic lupus
erythematosus; SSc, systemic sclerosis.
Kozu et al., Page 22
Supplementary material. The Japanese Pulmonary Circulation Study Group
Investigators
1. Collaborating hospitals and active investigators
Hiroaki Shimokawa (Department of Cardiovascular Medicine, Tohoku University Graduate School of
Medicine), Masaaki Ito (Department of Cardiology and Nephrology, Mie University Graduate School of
Medicine), Ken-ichi Hirata (Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe
University Graduate School of Medicine), Koichi Node (Department of Cardiovascular Medicine, Saga
University), Takuya Miyamoto (Department of Cardiology, Pulmonology, and Nephrology, Yamagata
University School of Medicine), Shuichi Ueno (Division of Cardiovascular Medicine, Department of
Medicine, Jichi Medical University School of Medicine), Hiroshi Watanabe (Department of Clinical
Pharmacology and Therapeutics , Hamamatsu University School of Medicine), Shinichi Hirotani
(Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine), Naohiko
Nakanishi (Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural
University of Medicine), Shuji Joho (Second Department of Internal Medicine, University of Toyama),
Tsutomu Saji (Department of Pediatrics, Toho University Medical Center Omori Hospital), Yamamuro
Megumi (Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto
University), Satoshi Yasuda (Department of Cardiovascular Medicine, National Cerebral and Cardiovascular
Center Hospital), Yoshihiro Fukumoto (Department of Cardiovascular Medicine, Kurume University
Graduate School of Medicine), Hiroshi Ito (Department of Cardiovascular Medicine, Okayama University
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences), Keijiro Saku (Department of
Cardiology, Fukuoka University School of Medicine), Takashi Miyauchi (Division of Cardiovascular
Medicine, Department of Clinical Medicine, Faculty of Medicine, University of Tsukuba), Rika Kawakami
(Department of Cardiovascular Medicine, Higashisumiyoshi Morimoto Hospital), Toyoaki Murohara
(Department of Cardiology, Nagoya University Graduate School of Medicine), Hidekazu Maruyama
(Department of Cardiology, Moriya Daiichi General Hospital).
2. Head office and coordinating center
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
Koichiro Sugimura, Tatsuo Aoki, Shunsuke Tatebe, Masanobu Miura, Saori Yamamoto, Nobuhiro Yaoita,
Hideaki Suzuki, Toru Shimizu, Haruka Sato, Ryo Konno, Yosuke Terui, Satoshi Miyata, Kotaro Nochioka,
Kimio Satoh, Shizuka Osaki, and Eiko Ishida.