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Kozu et al.,

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.,

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.,

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.,

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.,

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.,

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.,

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.,

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


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.,

Supplementary Table S6. Cox proportional hazards models including the number of

PH-specific drugs in PAH adjusted for the independent prognostic factors



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.,

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.,

Supplementary Table S8. Cox proportional hazards models of baseline variables in

PH-LHD



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.,

Supplementary Table S9. Cox proportional hazards models of baseline variables in CTEPH



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.,

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.,

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.,


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.,

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.,

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.,


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.,

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.,


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.,


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.,

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.

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