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Multi-institutional retrospective cohort study of patients with severe pulmonary hypertension associated with respiratory diseases NOBUHIRO TANABE,1,2 HIROYUKI TANIGUCHI,3 ICHIZO TSUJINO,4 FUMIO SAKAMAKI,5 NORIAKI EMOTO,6 HIROSHI KIMURA,7 KEI TAKAMURA,8 MASAYUKI HANAOKA,9 MASAHARU NISHIMURA4 AND KOICHIRO TATSUMI1 FOR THE JRS Lung Disease PH Study Group* Departments of 1Respirology and 2Advanced Medicine in Pulmonary Hypertension, Graduate School of Medicine, Chiba University, Chiba, 3Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Aichi, 4First Department of Medicine, Hokkaido University Hospital, Sapporo, 5Department of Medicine, Tokyo Saiseikai Central Hospital, Tokyo, 6 Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, 7Second Department of Internal Medicine, Nara Medical University, Kashihara, 8First Department of Medicine, Obihiro-Kosei General Hospital, Obihiro, 9First Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan

ABSTRACT Background and objective: Pulmonary hypertension (PH) is often associated with respiratory diseases, but only a small number of patients present with severe PH defined as mean pulmonary arterial pressure ≥ 35 mm Hg. We here conducted a multicenter, retrospective study of patients with severe PH associated with respiratory diseases (R-PH) to reveal their demographics, treatment, prognosis and determinants of prognosis. Methods: From 101 patients with severe R-PH collected by postal survey at the first stage, 70 patients with four major diseases (chronic obstructive pulmonary disease (COPD), combined pulmonary fibrosis with emphysema (CPFE), interstitial pneumonia associated with connective tissue disease (CTD-IP), interstitial pneumonia (IP)) and normal pulmonary arterial wedge pressure were studied for clinical characteristics, treatment and prognosis.

Correspondence: Nobuhiro Tanabe, Departments of Respirology and Advanced Medicine in Pulmonary Hypertension, Graduate School of Medicine, Chiba University, 1-8-1 Inohana Chuou-ku, Chiba 260-8670, Japan. Email: ntanabe@ faculty.chiba-u.jp *Members of JRS Lung Disease PH study group are listed in the Supplementary Information. Conflict of Interest Statement: NT is affiliated with the endowed department sponsored by Actelion Pharmaceuticals, and received a grant from the Japanese Respiratory Society and honoraria from Pfizer. HT, MH and MN received grants from the Ministry of Health, Labour and Welfare of Japan. NE received honoraria from Actelion Pharmaceuticals. HK received a grant from the Ministry of Health, Labour and Welfare of Japan and honoraria from Actelion Pharmaceuticals. KT received a grant from the Ministry of Health, Labour and Welfare of Japan and a grant from the Japanese Respiratory Society. Received 25 June 2014; invited to revise 15 September 2014; revised 5 November 2014; accepted 4 February 2015 (Associate Editor: Tamera Corte). Article first published online: 31 March 2015 © 2015 Asian Pacific Society of Respirology

SUMMARY AT A GLANCE We conducted a multi-institutional retrospective, observational study, focusing on severe pulmonary hypertension associated with respiratory diseases (mean pulmonary arterial pressure ≥ 35 mm Hg), and demonstrated a dismal prognosis overall with potential survival benefits for those who had received phosphodiseterase-5 inhibitors. These findings warrant future prospective randomized studies in this particular population.

Results: Three-year survival rates were 50% for COPD (n = 18), 35.7% for IP (n = 19) and 68.1% for CTD-IP (n = 20), and the 2-year survival rate for CPFE (n = 13) was only 22.6%. Eighty-one per cent of patients had been treated with pharmacotherapy specific for pulmonary arterial hypertension. Those patients who had received phosphodiesterase-5 inhibitors (PDE-5I) displayed significantly better survival from the date of diagnosis than those who had not (3-year survival: 61.8% vs 20.0% P < 0.0001), especially in the IP, CTD-IP and CPFE groups. Multivariate analysis also revealed that treatment with PDE-5I was a positive prognostic factor. Conclusions: We here demonstrated the dismal prognosis of patients with severe R-PH. The remarkably better survival in those patients who had received PDE-5I warrants and facilitates future prospective randomized studies in this particular population. Key words: chronic obstructive pulmonary disease, clinical respiratory medicine, nitric oxide, pulmonary circulation and pulmonary hypertension, pulmonary fibrosis. Abbreviations: % pred, % predicted; 6MWD, 6-min walk distance; BNP, brain natriuretic peptide; Card I, cardiac index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CPFE, combined pulmonary fibrosis and emphysema; Respirology (2015) 20, 805–812 doi: 10.1111/resp.12530

806 CTD-IP, interstitial pneumonia associated with connective tissue disease; DLCO, diffusing capacity of the lung for carbon monoxide; ERA, endothelin receptor antagonist; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HR, hazard ratio; IP, interstitial pneumonia; IPF, idiopathic pulmonary fibrosis; JRS, Japanese Respiratory Society; mod-Nice, modified Nice criteria; mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PAWP, pulmonary arterial wedge pressure; PDE-5I, phosphodiesterase-5 inhibitor; PFT, pulmonary function test; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; QOL, quality of life; R-PH, pulmonary hypertension associated with respiratory diseases; VC, vital capacity.

INTRODUCTION Past studies have shown that a small number of patients develop severe pulmonary hypertension (PH) associated with respiratory diseases (R-PH).1,2 According to the German consensus guidelines, at least two of the following criteria must be met for the diagnosis of severe PH: (i) mean pulmonary arterial pressure (mPAP) > 35 mm Hg; (ii) mPAP ≥25 mm Hg and cardiac index (Card I) < 2.0 L/min/m2; and (iii) pulmonary vascular resistance (PVR) > 6 Wood units and exclusion of other causes of PH.2 In the results of the summary of the 5th World PH Symposium (Nice Conference), either of the first two criteria of (i) mean pulmonary arterial pressure (mPAP) ≥ 35 mm Hg or (ii) mPAP ≥25 mm Hg and cardiac index (Card I) < 2.0 L/min/m2 was defined as severe PH.3 The mechanisms that cause severe PH in a certain subset of R-PH patients remain unknown. It has been suggested that, similar to pulmonary arterial hypertension (PAH), pulmonary vasoconstriction and vascular remodeling may underlie the pathogenesis and progression of R-PH.1 PH due to lung disease and/or hypoxaemia is categorized as group 3 PH,4 and the standard treatment is long-term oxygen therapy.5 PAH-specific pharmacotherapy has been introduced to treat R-PH in some cases, particularly with severe PH.6,7 However, there have been very few large-scale studies focusing on severe R-PH. One particular study could not show any differences in survival of the patients who were treated with PAH-specific therapy or not in severe PH due to chronic obstructive pulmonary disease (COPD).7 We conducted a multicenter, retrospective study of those patients with severe R-PH in an attempt to reveal their demographics, treatment and prognosis, and determinants of prognosis in patients with severe R-PH. We sent questionnaires to 855 hospitals that the Japanese Respiratory Society (JRS) approved as educational institutions,8 regarding their patients with severe R-PH. In Japan, we have some advantages in the use of PAH-specific therapy for patients with severe R-PH because they are allowed to be treated with financial support from the government once they are officially recognized as those with severe R-PH by the specific PH committee in each region.

METHODS Subjects Data from 101 patients with severe R-PH with mPAP ≥ 35 mm Hg were collected by postal survey at Respirology (2015) 20, 805–812

N Tanabe et al.

the first stage.8 Collaborators at 24 institutions completed additional studies (in February and May 2013) regarding baseline characteristics, diagnosis, treatment and prognosis in those patients with severe R-PH. We included consecutive patients who were diagnosed with severe R-PH without left heart disease after 2005 (bosentan was introduced in 2005 and sildenafil in 2008). Finally, 70 patients with four major underlying diseases (COPD (n = 18), combined pulmonary fibrosis and emphysema (CPFE) (n = 13), interstitial pneumonia associated with connective tissue disease (CTDIP) (n = 20), interstitial pneumonia (IP) (n = 19)), with normal pulmonary arterial wedge pressure (PAWP), and with a mean follow-up period of 1.9 ± 1.7 years were evaluated in the study (Table 1). Further details of the study’s inclusion criteria are described in Appendix S1.

Study design The study was designed as a retrospective cohort study of consecutive patients with severe R-PH treated by JRS-approved medical institutions. Measurements The following metrics were reviewed in each patient’s medical chart: pulmonary haemodynamics, % predicted vital capacity (VC %pred), % predicted forced expiratory volume in 1 s (FEV1 %pred), FEV1/forced vital capacity, % predicted transfer factor of the diffusing capacity of lung for carbon monoxide (DLCO), blood gas analysis while breathing room air, 6-min walk distance and various laboratory data. Because we did not include the patients with mPAP of 25–35 mm Hg and Card I < 2.0 L/min/m2, the patients were divided into two groups according to the modified Nice criteria (mod-Nice) based on the German consensus guidelines: severe mod-Nice-PH (Card I < 2 L/min/m2 or PVR > 6 Wood units) and less severe mod-Nice-PH (Card I ≥ 2 L/min/m2 and PVR ≤6 Wood units).2,3 Patients with impaired pulmonary function tests (PFT) were divided into two groups: mild (VC %pred ≥ 70 and FEV1 %pred ≥ 60) and severe PFT impairment (VC %pred < 70 or FEV1 %pred < 60) according to the classification of the Nice conference.3 Ethical considerations According to Japanese legislation, informed consent is not required for the collection of retrospective data. In this study, patients were de-identified and information was compiled according to the requirements of the Ministry of Health, Labour and Welfare, which is dedicated to privacy, information technology and civil rights in Japan. The study protocol was approved by the JRS board of directors in March 2012 and by the Research Ethics Committee of Chiba University School of Medicine (approval number 110). Survival analysis At the time of data collection, 32 of the 70 study participants were living and 38 were not. Survival from © 2015 Asian Pacific Society of Respirology

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Severe PH due to respiratory diseases Table 1 Baseline characteristics of patients with severe R-PH n Age (years) Gender (female/male) Brinkman index Classification of disease COPD CPFE CTD-IP IP mPAP (mm Hg) PAWP (mm Hg) Card I (L/min/m2) (n = 67) PVR (Wood units) (n = 68) Severe mod-Nice-PH (n = 68) Pa O2 (Torr) (n = 59) PaCO2 (Torr) (n = 59) VC %pred (n = 66) FEV1/FVC (%) (n = 66) FEV1 %pred (n = 64)

70 62 ± 11 20/50 852 ± 801 18 (26) 13 (18) 20 (19) 19 (27) 44 ± 10 9±4 2.8 ± 1.0 9.2 ± 4.3 52 (76) 55 ± 14 38 ± 9 75 ± 25 73 ± 19 66 ± 26

Mild PFT impairment (n = 66) DLCO %pred (n = 49) BNP (pg/mL) (n = 64) 6MWD (m) (n = 42) Treatment Oxygen therapy Warfarin Diuretics PAH-specific therapy Beraprost Epoprostenol ERA Bosentan Ambrisentan PDE-5I Sildenafil Tadalafil

26 (39) 28 ± 13 376 ± 504 231 ± 127 67 (96) 22 (31) 47 (70) 57 (81) 26 (37) 2 (3) 41 (59) 31 (44) 13 (19) 45 (64) 41 (59) 8 (13)

Mean ± SD or n (%). % pred, % predicted; 6MWD, 6-min walk distance; BNP, brain natriuretic peptide; Card I, cardiac index; COPD, chronic obstructive pulmonary disease; CPFE, combined pulmonary fibrosis and emphysema; CTD-IP, interstitial pneumonia associated with connective tissue disease; DLCO, diffusing capacity of the lung for carbon monoxide; ERA, endothelin receptor antagonist; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; IP, interstitial pneumonia; mod-Nice, modified Nice criteria; mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PAWP, pulmonary arterial wedge pressure; PDE-5I, phosphodiesterase-5; PFT, pulmonary function test; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; VC, vital capacity.

the date of the diagnostic catheterization demonstrating severe R-PH to death or to the final visit was compared between groups stratified by the following: PH severity using the mod-Nice criteria, degree of PFT impairment, treatment with each PAH-specific therapy and underlying lung diseases. The interval between the catheterization date and initiation of endothelin receptor antagonists (ERA) or phosphodiesterase-5 inhibitor (PDE-5I) was 0.3 ± 1.8 and 0.5 ± 1.1 years, respectively.

Statistical analysis Results are expressed as the mean ± standard deviation for continuous variables and as the number and percentage for categorical variables. Comparison between groups was performed by unpaired t-test for continuous variables and by chi-square test for categorical variables. Survival curves were analysed by the Kaplan–Meier method, and the Wilcoxon test was used to compare survival. Univariate and multivariate Cox proportional hazard models were used to examine prognostic factors. P values < 0.05 were considered statistically significant. All statistical analyses were performed using commercially available software (JMP 10.0.2, Japanese version, SAS Institute Inc., Tokyo, Japan).

RESULTS Baseline characteristics Baseline characteristics of the 70 patients with severe R-PH are shown in Table 1. PAH-specific therapy was used to treat 81% of patients. PDE-5I and ERA were used to treat 64% and 59% of patients, respectively. © 2015 Asian Pacific Society of Respirology

The decision to use PAH-specific therapy was independently made by physicians at each institution. Major reasons for not using PAH-specific therapy included the fact that these medications are not yet approved for treatment of R-PH and/or patient refusal (∼90%) or symptom improvement after oxygen therapy alone. Baseline clinical characteristics of the four groups are compared in Table 2. Additional data are included in the supplementary results.

Survival from the date of severe R-PH diagnosis Overall 1-, 3- and 5-year survival from the date of diagnosis was 74.2%, 47.2% and 27.3%, respectively (Fig. 1). Three-year survival rates were 50% for COPD (n = 18), 35.7% for IP (n = 19) and 68.1% for CTD-IP (n = 20), and the 2-year survival rate for CPFE (n = 13) was 22.6% (Fig. 2). Patients with CPFE had a significantly worse prognosis than patients with COPD (P = 0.03) or CTD-IP (P = 0.007). No significant differences in survival were observed between patients with scleroderma IP and patients with other forms of CTD-IP (3-year survival: 60% vs 80%, P = 0.52). No significant differences in survival were observed between patients with mild versus severe PFT impairment (P = 0.89), or in patients with severe or less severe mod-Nice-PH (P = 0.24). Comparisons of survival between the patients treated with or without PAH-specific therapy in the four major underlying diseases The patients with PAH-specific therapy survived significantly longer after the date of R-PH diagnosis than Respirology (2015) 20, 805–812

808 Table 2

N Tanabe et al. Baseline characteristics of patients categorized by four major underlying diseases

Age (years) Gender (female/male) Brinkman index mPAP (mm Hg) PAWP (mm Hg) Card I (L/min/m2) PVR (Wood units) Severe mod-Nice-PH PaO2 (Torr) PaCO2 (Torr) VC %pred FEV1/FVC (%) FEV1 %pred Mild PFT impairment DLCO %pred BNP (pg/mL) 6MWD (m) PAH-specific therapy Beraprost Epoprostenol ERA Bosentan Ambrisentan PDE-5I Sildenafil Tadalafil1

COPD (n = 18)

CPFE (n = 13)

CTD-IP (n = 20)

IP (n = 19)

67 ± 9 1/17* 1249 ± 741* 47 ± 15 10 ± 3** 2.7 ± 0.6 10.6 ± 5.8** 11 (65) 52 ± 16 39 ± 13 94 ± 27* 49 ± 17* 58 ± 33 8 (47) 29 ± 12 397 ± 608 263 ± 97** 14 (78) 7 (39) 0 (0) 8 (44) 5 (28) 4 (22) 14 (78) 12 (67) 3 (18)

64 ± 12 0/13* 1546 ± 674* 42 ± 5 9±3 2.4 ± 0.4 8.5 ± 2.3 12 (92) 59 ± 12 34 ± 8 80 ± 25** 79 ± 13* 77 ± 31 9 (69)** 21 ± 9** 223 ± 289** 140 ± 105** 10 (77) 4 (31) 0 (0) 7 (54) 6 (46) 1 (8) 9 (69) 8 (62) 1 (8)

60 ± 10 15/5* 221 ± 391* 44 ± 6 7 ± 3** 3.0 ± 1.6 9.9 ± 4.2 16 (80) 59 ± 14 36 ± 4 64 ± 15*,** 85 ± 10* 67 ± 19 5 (26)** 33 ± 16** 627 ± 621** 237 ± 117 19 (95) 12 (60)** 2 (10) 15 (75) 11 (55) 5 (25) 14 (70) 14 (74) 2 (13)

61 ± 13 4/15* 600 ± 665* 42 ± 8 9±4 2.8 ± 0.7 7.7 ± 3.4** 13 (72) 52 ± 13 41 ± 6 63 ± 19*,** 81 ± 12* 65 ± 18 4 (24)** 27 ± 10 236 ± 280** 271 ± 154** 14(74) 3 (16)** 0 (0) 11 (58) 9 (47) 3 (15) 8 (42) 7 (37) 2 (12)

*P < 0.01; **P < 0.05. % pred, % predicted; 6MWD, 6-min walk distance; BNP, brain natriuretic peptide; Card I, cardiac index; COPD, chronic obstructive pulmonary disease; CPFE, combined pulmonary fibrosis and emphysema; CTD-IP, interstitial pneumonia associated with connective tissue disease; DLCO, diffusing capacity of the lung for carbon monoxide; ERA, endothelin receptor antagonist; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; IP, interstitial pneumonia; mod-Nice, modified Nice criteria; mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PAWP, pulmonary arterial wedge pressure; PDE-5I, phosphodiesterase-5; PFT, pulmonary function test; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; VC, vital capacity.

patients who were not treated with PAH-specific therapy (3-year survival: 54.1% vs 12.6%, respectively, P = 0.006). There was no significant difference in survival between the patients treated with or without beraprost. However, patients treated with ERA survived significantly longer after the date of R-PH diagnosis than patients who were not treated with ERA (3-year survival: 52.6% vs 38.6%, respectively, P = 0.03). Similarly, those treated with PDE-5I survived significantly longer after the date of R-PH diagnosis than patients who were not treated with PDE-5I (3-year survival: 61.8% vs 20.0%, respectively, P < 0.0001) (Fig. 3). Further details are included in the supplementary information.

Figure 1 Survival curve from the date of Right heart catheterization in all patients with severe pulmonary hypertension associated with respiratory diseases (R-PH) (n = 93). Overall 1-, 3- and 5-year survival from the date of diagnosis was 74.2%, 47.2% and 27.3%, respectively.

Respirology (2015) 20, 805–812

Comparison of baseline characteristics of patients who were or were not treated with PDE-5I Patients treated with PDE-5I were more often classified into the mild PFT impairment group than patients who were not treated with this class of medication (51% vs 14%, respectively, P < 0.01). No other significant differences were observed between © 2015 Asian Pacific Society of Respirology

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patients who were not treated with PDE-5I (2-year survival: 64.2% (n = 34) vs 14.9% (n = 18), respectively, P < 0.0001). However, in the patients with less severe mod-Nice-PH, there was no significant difference in survival between the patients with or without PDE-5I (3-year survival: 64.8% (n = 10) vs 44.4% (n = 6), respectively, P = 0.24). mPAP and PVR were lower, but PAWP was higher in patients with less severe modNice-PH than in those with severe mod-Nice-PH (mPAP: 38 ± 3 mm Hg vs 46 ± 10 mm Hg, P = 0.005; PVR 5 ± 1 vs 11 ± 4 Wood units, P < 0.0001; PAWP: 10 ± 3 vs 8 ± 3 mm Hg, P = 0.008). In patients subcategorized by CPFE, CTD-IP or IP, treatment with PDE-5I was also associated with significantly improved survival. Further details are included in the supplementary results and Figures S1–S4. Figure 2 Survival curves based on underlying pulmonary disease. Three-year survival was 50% (chronic obstructive pulmonary disease (COPD), n = 18, —), 35.7% (interstitial pneumo) and 68.1% (interstitial pneumonia associated nia (IP), n = 19, ), and 2-year with connective tissue disease (CTD-IP), n = 20, survival rate was 22.6% (combined pulmonary fibrosis and ). Patients with CPFE had a signifiemphysema (CPFE), n = 13, cantly worse prognosis than patients with COPD (P = 0.03) or CTD-IP (P = 0.007).

Prognostic factors in patients with severe R-PH Univariate analysis revealed that younger age, PDE-5I treatment and a diagnosis of CTD-IP or COPD (compared with CPFE) were significantly associated with improved survival after the diagnosis of R-PH. mPAP, Card I, PVR, partial arterial oxygen concentration and DLCO were not associated with improved survival. Similarly, multivariate analysis revealed that PDE-5I treatment and a diagnosis of CTD-IP or COPD (relative to CPFE) were independently associated with improved survival (Table 4). When PDE-5I and ERA treatments were included in this model, only PDE-5I was associated with improved survival.

DISCUSSION

Figure 3 Comparison of survival after diagnosis of severe pulmonary hypertension associated with respiratory diseases (R-PH) in patients with or without phosphodiesterase-5 inhibitor (PDE-5I). More patients treated with PDE-5I (n = 45) survived to 3 years after diagnosis than patients who were not treated with PDE-5I (n = 25) (61.8 vs 20.0%, respectively, P < 0.0001). Gray lines, without PDE-5I; Black lines, with PDE-5I.

patients who were or were not treated with PDE-5I (Table 3).

Use of PDE-5I and survival in subcategorized patients In patients with severe mod-Nice-PH, those treated with PDE-5I survived significantly longer than © 2015 Asian Pacific Society of Respirology

In this first multicenter survey of severe R-PH in Japan, we collected data from 70 patients and elucidated their demographics, treatment regimens, prognosis and its predictive factors. Although the overall prognosis was dismal, we unexpectedly found that those patients who had received PDE-5I had significantly better survival from the date of diagnosis of severe R-PH compared with those who had not. This was particularly true for patients with CPFE, IP or CTD-IP. Multivariate analysis revealed that treatment with PDE-5I was an independent positive prognostic factor. Although this was a retrospective observational cohort study, these findings may warrant and facilitate future prospective, randomized and placebo-controlled studies in this particular population who display severe R-PH (mPAP ≥ 35 mm Hg). There are a number of limitations inherent in this study because of the study design, which would include its retrospective, descriptive and observational nature. In addition, the sample size was small in each disease category. Furthermore and more importantly, selection bias could not be ignored because any decision to use PAH-specific therapy was made by physicians themselves at each institution. Despite the reports that worsening of gas exchange and quality of life (QOL) might occur with use of ERA and PDE-5I in R-PH patients,9,10 we did not evaluate any possible adverse gas exchange effects or Respirology (2015) 20, 805–812

810 Table 3

N Tanabe et al. Baseline characteristics of patients with four major underlying diseases categorized by PDE-5I treatment

Age (years) Gender (female/male) Brinkman index mPAP (mm Hg) PAWP (mm Hg) Card I (L/min/m2) PVR (Wood units) Severe mod-Nice-PH PaO2 (Torr) PaCO2 (Torr) VC %pred FEV1/FVC (%) FEV1 %pred Mild PFT impairment DLCO %pred BNP (pg/mL) 6MWD (m) Beraprost ERA

With PDE-5I (n = 45)

Without PDE-5I (n = 25)

P

62 ± 10 14/31 874 ± 804 44 ± 10 9±3 2.7 ± 0.7 9.5 ± 4.3 34 (78) 54 ± 14 37 ± 9 78 ± 26 73 ± 18 70 ± 26 23 (51) 28 ± 13 378 ± 451 231 ± 119 20 (45) 30 (67)

64 ± 13 6/19 807 ± 816 44 ± 9 9±4 2.9 ± 1.4 8.7 ± 4.2 18 (75) 57 ± 14 38 ± 7 67 ± 21 73 ± 22 58 ± 25 3 (14) 28 ± 12 372 ± 604 232 ± 165 6 (24) 11 (44)

ns ns ns ns ns ns ns ns ns ns ns ns ns 485 dyn/s/cm5.18 In scleroderma IP patients, 3-year survival (60%) was higher than that in Mathai et al.’s study (39%).19 Better survival in our series might be partly related to the frequent use of PAH-specific therapy including PDE-5I. In conclusion, this study confirmed that COPD, CPFE, CTD-IP and IP were major underlying lung diseases of severe R-PH and their prognosis was dismal overall. From our experience with the frequent use of PAH-specific pharmacotherapy for those patients, we found possible survival benefits for PDE-5I. A future randomized placebo-controlled study would definitely be required to demonstrate the efficacy of PDE-5I treatment in this specific population.

Acknowledgements We thank all doctors of the JRS Lung Disease PH Study group listed in Appendix S2 for their contribution to this study. This study was partly supported by a grant from the Pulmonary Circulation/Lung Injury Assembly of the Japanese Respiratory Society and by a grant from the Respiratory Failure Research Group of the Ministry of Health, Labour and Welfare of Japan.

REFERENCES 1 Chaouat A, Naeije R, Weitzenblum E. Pulmonary hypertension in COPD. Eur. Respir. J. 2008; 32: 1371–85. 2 Hoeper MM, Andreas S, Bastian A, Claussen M, Ghofrani HA, Gorenflo M, Grohé C, Günther A, Halank M, Hammerl P et al. Pulmonary hypertension due to chronic lung disease: updated Recommendations of the Cologne Consensus Conference 2011. Int. J. Cardiol. 154(Suppl. 1): S45–53. 3 Seeger W, Adir Y, Barberà JA, Champion H, Coghlan JG, Cottin V, De Marco T, Galiè N, Ghio S, Gibbs S et al. Pulmonary hypertension in chronic lung diseases. J. Am. Coll. Cardiol. 2013; 62(25 Suppl. ): D109–16. 4 Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, Gomez Sanchez MA, Krishna Kumar R, Landzberg M, Machado RF et al. Updated clinical classification of pulmonary hypertension. J. Am. Coll. Cardiol. 2013; 62(25 Suppl.): D34–41. 5 Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur. Respir. J. 2009; 34: 1219–63. 6 Hurdman J, Condliffe R, Elliot CA, Davies C, Hill C, Wild JM, Capener D, Sephton P, Hamilton N, Armstrong IJ et al. ASPIRE registry: assessing the spectrum of pulmonary hypertension identified at a REferral centre. Eur. Respir. J. 2012; 39: 945–55. 7 Hurdman J, Condliffe R, Elliot CA, Swift A, Rajaram S, Davies C, Hill C, Hamilton N, Armstrong IJ, Billings C et al. Pulmonary hypertension in COPD: results from the ASPIRE registry. Eur. Respir. J. 2013; 41: 1292–301. 8 Tanabe N, Taniguchi H, Tsujino I, Sakamaki F, Emoto N, Kimura H, Miyaji K, Takamura K, Hayashi S, Hanaoka M et al. Current trends in the management of pulmonary hypertension associated with respiratory disease in institutions approved by the Japanese Respiratory Society. Respir. Investig. 2014; 52: 167–72. 9 Stolz D, Rasch H, Linka A, Di Valentino M, Meyer A, Brutsche M, Tamm M. A randomised, controlled trial of bosentan in severe COPD. Eur. Respir. J. 2008; 32: 619–28. 10 Blanco I, Gimeno E, Munoz PA, Pizarro S, Gistau C, Rodriguez-Roisin R, Roca J, Barberà JA. Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Am. J. Respir. Crit. Care Med. 2010; 181: 270–8. Respirology (2015) 20, 805–812

812 11 Scharf SM, Iqbal M, Keller C, Criner G, Lee S, Fessler HE. National Emphysema Treatment Trial (NETT) Group: hemodynamic characterization of patients with severe emphysema. Am. J. Respir. Crit. Care Med. 2002; 166: 314–22. 12 Hinchcliff M, Desai CS, Varga J, Shah SJ. Prevalence, prognosis, and factors associated with left ventricular diastolic dysfunction in systemic sclerosis. Clin. Exp. Rheumatol. 2012; 30(2 Suppl. 71): S30–7. 13 Papadopoulos CE, Pitsiou G, Karamitsos TD, Karvounis HI, Kontakiotis T, Giannakoulas G, Efthimiadis GK, Argyropoulou P, Parharidis GE, Bouros D. Left ventricular diastolic dysfunction in idiopathic pulmonary fibrosis: a tissue Doppler echocardiographic [corrected] study. Eur. Respir. J. 2008; 31: 701–6. 14 López-Sánchez M, Muñoz-Esquerre M, Huertas D, GonzalezCostello J, Ribas J, Manresa F, Dorca J, Santos S. High prevalence of left ventricle diastolic dysfunction in severe COPD associated with a low exercise capacity: a cross-sectional study. PLoS ONE 2013; 8: e6803. 15 Mittoo S, Jacob T, Craig A, Bshouty Z. Treatment of pulmonary hypertension in patients with connective tissue disease and interstitial lung disease. Can. Respir. J. 2010; 17: 282–6. 16 The Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N. Engl. J. Med. 2010; 363: 620–8. 17 Han MK, Bach DS, Hagan PG, Yow E, Flaherty KR, Toews GB, Anstrom KJ, Martinez FJ. IPFnet Investigators: sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest 2013; 143: 1699–708. 18 Cottin V, Le Pavec J, Prévot G, Mal H, Humbert M, Simonneau G, Cordier JF, GERM″O″P. Pulmonary hypertension in patients with combined pulmonary fibrosis and emphysema syndrome. Eur. Respir. J. 2010; 35: 105–11. 19 Mathai SC, Hummers LK, Champion HC, Wigley FM, Zaiman A, Hassoun PM, Girgis RE. Survival in pulmonary hypertension associated with the scleroderma spectrum of diseases: impact of interstitial lung disease. Arthritis Rheum. 2009; 60: 569–77.

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N Tanabe et al. Supplementary Information Additional Supplementary Information can be accessed via the html version of this article at the publisher’s web-site: Supplementary Figure S1 Comparison of survival between patients with chronic obstructive pulmonary disease (COPD) who were or were not treated with phosphodiesterase-5 inhibitor (PDE-5I). Treatment with PDE-5I had no significant effect on survival after the date of diagnosis of severe pulmonary hypertension associated with respiratory diseases (R-PH) in patients with COPD (3-year survival: 53.6% vs 37.5%, P = 0.56). Supplementary Figure S2 Comparison of survival between patients with combined pulmonary fibrosis and emphysema (CPFE) who were or were not treated with phosphodiesterase-5 inhibitor (PDE-5I). Treatment with PDE-5I was associated with significantly longer survival in this patient population (2-year survival: 34% vs 0%, P = 0.008). Supplementary Figure S3 Comparison of survival between patients with interstitial pneumonia associated with connective tissue disease (CTD-IP) who were or were not treated with phosphodiesterase-5 inhibitor (PDE-5I). Treatment with PDE-5I was associated with significantly longer survival in this patient population (3-year survival: 83.9% vs 33.3%, P = 0.004). Supplementary Figure S4 Comparison of survival between patients with interstitial pneumonia (IP) who were or were not treated with phosphodiesterase-5 inhibitor (PDE-5I). Treatment with PDE-5I was associated with significantly longer survival in this patient population (3-year survival: 68.6% vs 0%, P = 0.02). Supplementary Appendix S1 Methods. Supplementary Appendix S2 The Japanese Respiratory Society (JRS) Lung Disease PH Study Group.

© 2015 Asian Pacific Society of Respirology

Multi-institutional retrospective cohort study of patients with severe pulmonary hypertension associated with respiratory diseases.

Pulmonary hypertension (PH) is often associated with respiratory diseases, but only a small number of patients present with severe PH defined as mean ...
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