Clinical Practice of Pulmonary Arterial Hypertension (PAH) and Potential Barriers to Intensive Treatment Among PAH‐Specialized and Non‐PAH‐Specialized Centers in Japan

ABSTRACT

Pulmonary arterial hypertension (PAH) is a rare and progressive disease characterized by remodeling of the pulmonary vasculature, which leads to increased pulmonary artery pressure and ultimately right ventricular failure. Although Japanese guidelines recommend combination therapy, real‐world data show inconsistencies in its implementation. We thus conducted a cross‐sectional, web‐based questionnaire survey to understand the recent real‐world clinical practices in Japan and identify factors associated with treatment decisions, with a particular focus on the use of combination therapies. The findings indicated that oral PAH medications were widely available and commonly prescribed, whereas inhaled and parenteral infusion therapy were less accessible and used less frequently. Moreover, physicians working in PAH‐specialized centers were significantly more likely to prescribe parenteral infusion therapies (adjusted odds ratio [aOR] = 2.6, 95% confidence interval [CI]: 1.5–4.3, p < 0.001) and adopt dual (aOR = 3.0, 95% CI: 1.4–6.5, p = 0.01) or triple combination regimens (aOR = 2.7, 95% CI: 1.5–2.7, p < 0.001). Physicians with experience treating high risk patients at PAH‐specialized centers were also significantly more likely to prescribe parenteral infusion therapies (aOR = 3.5, 95% CI: 1.8–6.6, p < 0.001) and adopt dual (aOR = 5.9, 95% CI: 2.5–14.2, p < 0.001) or triple combination regimens (aOR = 3.4, 95% CI: 1.7–6.7, p < 0.001). This study revealed differences in clinical practice between PAH‐specialized and non‐specialized centers in real‐world settings. Management of PAH at PAH‐specialized centers was associated with increased treatment intensification, indicating the need for enhanced collaboration between PAH‐specialized and non‐specialized centers to ensure optimal care for patients with PAH.

1. Introduction

Pulmonary arterial hypertension (PAH; World Health Organization [WHO] Group 1) is a rare and progressive disease characterized by thickening of pulmonary vascular walls and is associated with poor prognosis and a significant impact on quality of life (QoL). There are several subtypes of PAH, including idiopathic PAH (IPAH), heritable PAH (HPAH), PH associated with connective tissue diseases (CTD‐PAH), PH associated with congenital heart disease (CHD‐PAH), portopulmonary hypertension (PoPH), drug or toxin induced PH (DPH), and PAH associated with HIV or schistosomiasis. Among these, IPAH is the most commonly observed subtype. Pulmonary vascular remodeling is a hard core of PAH pathophysiology, which leads to an increase of mean pulmonary arterial pressure (mPAP) and right ventricular afterload, followed by progressive right ventricular dysfunction and heart failure [1, 2]. According to a recent systematic review, estimated incidence of PAH among adult ranged from 1.5 to 32 per million and prevalence from 12.4 to 268 per million population worldwide, and is two to four times more common among females than males [3, 4]. In Japan, it has been estimated that the prevalence is approximately 32 per million population [5]. The overall 5‐year survival rate has been estimated to be approximately 60% [6].

Over the past two decades, a number of novel oral, injectable, and inhaled drugs for PAH have been approved by regulatory authorities. These include five classes of drugs that target three main signaling pathways; endothelin receptor antagonists (ERA), phosphodiesterase type 5 inhibitors (PDE5i), soluble guanylate cyclase activators (sGC), prostacyclin analogues, and prostacyclin receptor agonists [1]. According to the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines on pulmonary hypertension, using combination therapy to target multiple pathogenic pathways is now considered the standard of care for PAH [7, 8], supported by strong evidence from numerous randomized controlled studies and observational studies [9].

In Japan too, a guideline published by the Japanese Circulation Society (JCS) in 2017 and updated in 2021 [10], recommends combination therapy for patients diagnosed with IPAH and HPAH who are at low to high risks without cardiopulmonary comorbidities [11]. The recommendation has been supported by several clinical trials showing better prognosis in combination therapy rather than monotherapy (Note that the JCS guideline was updated in March 2025 to add the activin signaling inhibitor as the fourth therapeutic pathway. This study, however, references the 2021 JCS guideline because it was the version in effect during the study period) [12, 13], as well as data from two Japanese registry data such as the Japan Pulmonary Hypertension Registry (JAPHR) [14] and Japanese Pulmonary Circulation Study Group [15]. Both registry data have shown that approximately 80% of registered PAH patients received initial combination therapy and that 5‐year survival rate was 74%, higher than the global average of 55% [16, 17, 18, 19, 20].

Although Japanese registry data indicated better outcomes among patients receiving combination therapies, the reported proportions of patients on combination therapy versus monotherapy were inconsistent between registry data and real‐world studies. The latest JAPHR data (2016–2020) suggested that approximately 80% of registered PAH patients received initial combination therapy and 20% received initial monotherapy [14]. In contrast, real‐world studies—such as an administrative claims database analysis (2008–2020) [21] and disease‐specific program (DSP) from Adelphi Real World (ARW) Japanese study [22] reported that approximately 30%–34% of PAH patients received combination therapy, while 57%–66% received initial monotherapy. JAPHR primarily involves PAH‐specialized centers, the importance of analyzing differences in treatment strategies with respect to varying levels of specialization in PAH care has been highlighted in these studies.

Similarly, despite the critical role of parenteral infusion therapies in managing high‐risk PAH patients [2, 10], evidence of their utilization remains notably limited in real‐world clinical practice in Japan. According to JAPHR registry data, parenteral prostacyclin analogs such as epoprostenol have demonstrated significant survival benefits, yet their adoption outside PAH‐specialized centers has been constrained by factors including administration complexity and patient burden [23]. The 2017 Japanese Circulation Society guidelines also emphasize the importance of parenteral infusion prostacyclin therapy for high‐risk cases but acknowledge that real‐world implementation is often inconsistent due to logistical and clinical challenges [10] suggesting a gap between guideline recommendations and actual prescribing behavior.

This study was designed to describe the current landscape of PAH care in Japan and to clarify real‐world differences between PAH‐specialized and non‐specialized centers. Building on existing real‐world evidence, this study seeks to further understand inconsistencies in treatment patterns and to more clearly define the barriers and drivers guiding physicians' therapeutic decisions. These gaps challenge our understanding to recognize unmet medical needs and develop practical clinical solutions. To capture qualitative insights while adding quantitative rigor, we conducted a physician survey and complemented it with logistic regression analysis. This approach corroborates qualitative findings with quantitative evidence, allowing a depiction of decision‐making in routine practice.

2. Methods

2.1. Study Design and Participants

This study was a non‐interventional, cross‐sectional study whereby physicians were invited to take part in an online questionnaire survey on treatment and management of PAH patients. The physicians were recruited via a commercial panel, and were required to fulfill the following inclusion criteria: (1) treated at least one adult PAH patient (≥ 18 years old) using PAH ‐targeted drugs in the last 5 years; (2) experienced prescribing and determining PAH treatment in the last 5 years; and (3) primarily affiliated with the following departments at their current facilities: respiratory internal medicine/cardiovascular internal medicine/pediatric cardiology/rheumatology/internal medicine for connective tissue/dermatology and specializing in these areas within general internal medicine.

The questionnaire consisted of a total of 37 closed‐ended questions, under the following major themes: “demographic characteristics of the participants,” “clinical experience in PAH treatment and management,” and “treatment preferences.” The questionnaire was designed to be completed in approximately 15 min.

2.2. Data Collection and Analysis

The on‐line questionnaire was made available for participation for 15 days in September 2024, via multiple digital devices (e.g., PC and mobile devices such as smartphones and tablets). Potential participants were first asked to give their consent to participate via the questionnaire website, and only those who gave informed consent were able to proceed. Participants were then required to answer the questionnaire in a fixed order (i.e., they were not allowed to go back to the previous questions). All items had to be answered before submission, ensuring completeness of the responses.

To describe the landscape of treatment and management of PAH in Japan, a descriptive analysis was performed, with continuous variables reported as numbers and proportions in each category. We also collected information regarding availability of PAH drugs at participants' facilities (i.e., drug stock) and their personal experience of prescribing drugs, from which prescription rates were calculated (prescription rate = no. who responded that they have personal experience of prescribing PAH drug/no. who responded that the drug was available at their facility × 100).

Furthermore, logistic regression analysis was conducted whereby three models were constructed to explore potential factors related to the following outcomes, (1) use of parenteral infusion therapies versus never‐use of parenteral infusion therapies, (2) monotherapy vs dual or more than dual therapy, and (3) dual therapy vs triple or more than triple therapy.

We aimed to evaluate the participants' clinical experience by whether they work at a PAH‐specialized center as well as their personal experience of treating patients in terms of the number of patients seen in the past 5 years (1 to 9/10 or more), and frequency of seeing patients. To capture the frequency of seeing patients, responses were categorized along three axes: (i) the number of PAH patients seen in the past 5 years, (ii) the average frequency of visits for these patients, and (iii) the average follow‐up interval across all patients seen during this period. Respondents were stratified a priori into two groups: those who had seen 10 or more patients and those who had seen less than 10 patients. Physicians were classified as “regular” if they treated 10 or more PAH patients with follow‐up interval every 6 months or more, or less than 10 patients with patients visiting every 3 months or more. They were classified as “occasional” if they treated 10 or more patients with follow‐up intervals of less than every 6 months, or less than 10 patients with patients visiting less than every 3 months. This threshold is consistent with clinical practice guidelines in Japan, where routine PAH follow‐up is typically conducted every 3–6 months.

Other dependent variables included experience of seeing high‐risk patients (yes/no), experience of seeing patients with comorbidities (yes/no), experience of seeing patients with various initial levels of mPAP at 31–40, 41–50, and ≥ 51 mmHg (yes/no), and availability of collaboration with other departments or facilities (yes/no). Results were expressed as adjusted odds ratios (aOR) and their 95% confidence intervals (CI). A two‐sided p‐value of < 0.05 was considered statistically significant.

All statistical analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA).

3. Results

3.1. Demographic Characteristics and Clinical Experience of the Participants

In total, 1245 potential participants were screened. Exclusions were as follows: 25 for employment or consultancy with pharmaceutical companies within the past 5 years; 145 for lack of experience treating at least one adult PAH patient with PAH‐targeted drugs in the past 5 years; 510 for no experience prescribing or determining PAH treatment; 44 for non‐affiliation with relevant departments (respiratory medicine, cardiovascular medicine, pediatric cardiology, rheumatology, internal medicine for connective tissue diseases, or dermatology); and 28 who declined consent. Of the remaining 493, 400 met the clinical department allocation criteria, and 93 were excluded. Consequently, therefore, 400 physicians were included in the analyses (Figure 1). Among them, 88.5% (n = 354) were male and 47.5% (n = 190) were aged between 29 and 44 years. 37.0% (n = 148) were employed at PAH‐specialized centers, as recognized by the JPCPHS (Table 1).

Figure 1.

Attribution diagram. Flowchart illustrating the selection and inclusion process of participants in the study. PAH, pulmonary arterial hypertension.

Table 1.

Basic characteristics of the participants (n = 400).

	n	%
TOTAL	400	100.0
Sex
Male	354	88.5
Female	39	9.8
Others	7	1.8
Age group (years)
29–44	190	47.5
45–64	185	46.3
65 or older	25	6.3
Works at a PAH‐specialized center
Yes	148	37.0
No	252	63.0
Affiliation 1 (clinical department)
Cardiology	109	27.3
Pulmonology	105	26.3
General internal medicine	57	14.3
Collagen diseases internal medicine	43	10.8
Dermatology	30	7.5
Pediatric cardiology	28	7.0
Rheumatology	28	7.0
Affiliation 2 (type of medical facility)
Clinics	41	10.3
General hospitals	148	37.0
Public hospitals	96	24.0
University hospitals	115	28.8

The clinical experience of the 400 physicians in treating PAH patients in the past 5 years is summarized in Table 2. The proportion of those who had treated 10 or more patients was greater among those who were employed at PAH‐specialized center, compared to non‐PAH‐specialized center (73/148, 49.3% vs. 57/252, 22.6%). The proportion of those who frequently followed up patients (regularly) was slightly higher among those who were employed at PAH‐specialized center, compared to non PAH‐specialized center (141/148, 95.3% vs. 224/252, 88.9%). While 73.5% (n = 294) and 68.0% (n = 272) of the participants reported having experienced treating patients diagnosed with IPAH and CTD‐PAH, respectively, fewer than 10% had treated patients with DPAH (9.3%, n = 37) and HIV/schistosomiasis‐related PAH (4.5%, n = 18). Regarding comorbid conditions, 80.8% (n = 323) had treated patients with at least one of the following: obesity, hypertension, diabetes mellitus, coronary heart disease, or atrial fibrillation, and 70.0% (n = 280) had experience treating patients who have suspected pulmonary veno‐occlusive disease (PVOD), a diffusing capacity of the lung for carbon monoxide (%DLCO < 45), or smoking history. Additionally, 60.8% (n = 243) reported they had experience treating patients without any of the comorbid conditions described above. More than 80% of the participants had experienced treating low‐ or medium‐risk PAH patients; however, only 60.3% (n = 241) had experience treating high‐risk PAH patients. Regarding initial mPAP of patients, over 70% of the participants had experienced treating patients whose initial mPAP ranged from 25 to 40 mmHg. The proportion of participants who experienced managing patients with each range of initial mPAP values declined as the mPAP increased. Specifically, 33.3% (n = 133) had managed patients whose initial mPAP exceeded 51 mmHg (Table 2).

Table 2.

Experience of treating PAH patients by selected characteristics (n = 400).

	All participants		PAH‐specialized center		Non PAH‐specialized center
	n	%	n	%	n	%
TOTAL	400	100	148	100	252	100
No. patients treated in the past 5 years
1 ~ 9	270	67.5	75	50.7	195	77.4
10 or more	130	32.5	73	49.3	57	22.6
Frequency of following‐up patients
Occasionally	35	8.8	7	4.7	28	11.1
Regularly	365	91.3	141	95.3	224	88.9
Have treated patients with the following diagnosisa
IPAH	294	73.5	121	81.8	173	68.7
HPAH	86	21.5	61	41.2	25	9.9
CTD‐PAH	272	68.0	113	76.4	159	63.1
CHD‐PAH	141	35.3	75	50.7	66	26.2
PoPH	91	22.8	43	29.1	48	19.0
DPAH	37	9.3	24	16.2	13	5.2
HIV/Schistosomiasis‐related PAH	18	4.5	15	10.1	3	1.2
Unknown	75	18.8	28	18.9	47	18.7
Have treated patients with the following comorbid conditions
1. Any one of the following: obesity, hypertension, DM, CHD, atrial fibrillation	323	80.8	132	89.2	191	75.8
2. All of the following: suspected PVOD, %DLCO < 45, smoking history	280	70.0	115	77.7	165	65.5
Both 1 and 2	219	54.8	95	64.2	124	49.2
Neither 1 nor 2	243	60.8	100	67.6	143	56.7
Unknown	64	16.0	24	16.2	40	15.9
Have treated patients with the following risk evaluations
Low	334	83.5	133	89.9	201	79.8
Medium	332	83.0	132	89.2	200	79.4
High	241	60.3	107	72.3	134	53.2
Unknown	36	9.0	14	9.5	22	8.7
Have treated patients with the following initial mPAP (mmHg)
Below 24	200	50.0	90	60.8	110	43.7
25–30	290	72.5	124	83.8	166	65.9
31–40	290	72.5	124	83.8	166	65.9
41–50	214	53.5	95	64.2	119	47.2
51 or above	133	33.3	68	45.9	65	25.8
Unknown	33	8.3	8	5.4	25	9.9

Abbreviations: CHD, coronary heart disease; CTD PAH, connective tissue disease‐PAH; DLCO, Diffusion Capacity of the Lung for Carbon Monoxide; DM, diabetes mellitus; HPAH, Hereditary PAH; HIV, Human Immunodeficiency Virus; IPAH, Idiopathic PAH; mPAP, mean Pulmonary Artery Pressure; PAH, Pulmonary Arterial Hypertension; PoPH, Portal hypertension PAH; PVR, pulmonary vascular resistance.

^a Percentages may not sum to 100% because individual physicians could report multiple diagnoses.

3.2. Availability of and Personal Experience of Prescribing PAH Drugs

The availability of PAH drugs at participants' facilities, their personal experience in prescribing each drug, and in combination, and prescription rates are described in Table 3. Approximately 70% of the participants reported that oral PAH medicines, including ERA, nitric oxide (NO) pathway and oral prostacyclin, were available at their facilities. In contrast, 48.3% (n = 193) and 44.5% (n = 178) of participants responded that parenteral infusion prostacyclin and inhaled prostacyclin were available, respectively. The proportions were nearly twice as high in PAH‐specialized centers, with the availability of parenteral infusion prostacyclin and inhaled prostacyclin reported by 69.6% (n = 103) and 63.5% (n = 94), respectively, compared with 35.7% (n = 90) and 33.3% (n = 84) of participants in non‐PAH‐specialized centers.

Table 3.

Situation of drug inventory and the actual experience in prescribing selected drugs and combinations for adult PAH patients (n = 400).

	All participants (n = 400)					PAH‐specialized center (n = 148)						Non PAH‐specialized center (n = 252)
	Included in the hospital drug inventory (a)		Have personally experienced prescribing (b)		Prescription rate % (b)/(a) × 100	Included in the hospital drug inventory (a)			Have personally experienced prescribing (b)		Prescription rate % b)/(a) × 100	Included in the hospital drug inventory (a)		Have personally experienced prescribing (b)		Prescription rate % (b)/(a) × 100
	n	%	n	%		n	%	n		%		n	%	n	%
Drugs
ERA	317	79.3	273	68.3	86.1	122	82.4	109		73.7	89.3	195	77.4	164	65.1	84.1
NO pathway (PDE5i, sGC stimulators)	285	71.3	267	66.8	93.7	111	75.0	106		71.6	95.5	174	69.1	161	63.9	92.5
Oral prostacyclin	342	85.5	261	65.3	76.3	134	90.5	101		68.2	74.4	207	82.1	160	63.5	77.3
Parenteral infusion prostacyclina	193	48.3	117	28.5	60.6	103	69.6	68		46.0	66.0	90	35.7	49	19.4	54.4
Inhaled prostacyclin	178	44.5	114	29.3	64.0	94	63.5	73		49.3	77.7	84	33.3	41	16.3	48.8
Combinations
ERA + NO pathway	NA	NA	174	43.5	NA	NA	NA	82		55.4	NA	NA	NA	92	36.5	NA
ERA + oral prostacyclin	NA	NA	167	41.8	NA	NA	NA	73		49.3	NA	NA	NA	93	36.9	NA
ERA + inhaled prostacyclin	NA	NA	79	19.8	NA	NA	NA	46		31.1	NA	NA	NA	33	13.1	NA
ERA + parenteral infusion prostacyclin a	NA	NA	89	22.3	NA	NA	NA	51		34.5	NA	NA	NA	38	15.1	NA
NO pathway + oral prostacyclin	NA	NA	164	41.0	NA	NA	NA	80		54.1	NA	NA	NA	84	33.3	NA
NO pathway + inhaled prostacyclin	NA	NA	85	21.3	NA	NA	NA	51		34.5	NA	NA	NA	34	13.5	NA
NO pathway + parenteral infusion prostacyclin a	NA	NA	75	18.8	NA	NA	NA	45		30.4	NA	NA	NA	30	11.9	NA
ERA + NO pathway + oral prostacyclin	NA	NA	151	37.8	NA	NA	NA	76		51.4	NA	NA	NA	75	29.8	NA
ERA + NO pathway + inhaled prostacyclin	NA	NA	77	19.3	NA	NA	NA	43		29.1	NA	NA	NA	34	13.5	NA
ERA + NO pathway + parenteral infusion prostacyclin a	NA	NA	63	15.8	NA	NA	NA	39		26.4	NA	NA	NA	24	9.5	NA
Other	NA	NA	7	1.8	NA	NA	NA	1		0.7	NA	NA	NA	6	2.4	NA

Abbreviations: ERA, Endothelin Receptor Antagonists; IV, Intravenous; NA, not applicable; NO, Nitric Oxide; PAH, Pulmonary Arterial Hypertension; PDE‐5i, phosphodiesterase type 5 inhibitor; SC, Subcutaneous.

^a Intravenous and subcutaneous.

A similar pattern was observed in the participants' own experience in prescribing PAH medications. While the prescription rate of oral PAH medications exceeded 75%, the rate for parenteral infusion prostacyclin and inhaled prostacyclin were 60.6% and 64.0%, respectively. The prescription rates for oral PAH medications were similar among specialized and non‐PAH‐specialized centers; however, the rates for parenteral infusion prostacyclin and inhaled prostacyclin were higher in PAH‐specialized centers, at 66.0% and 77.7%, compared with 54.4% and 48.8% in non‐PAH‐specialized centers.

Likewise, the proportion of those who have experienced dual therapy of oral medications was approximately twice as high as those who have experienced dual therapy involving parenteral infusion prostacyclin or inhaled prostacyclin (e.g., 43.5% for ERA and NO pathway, 19.8% for ERA and inhaled prostacyclin). Even smaller proportion had experienced triple therapy – for example, 37.8% had experienced ERA, NO pathway and oral prostacyclin, however the proportion further dropped to 15.8% for those experiencing ERA, NO pathway and parenteral infusion prostacyclin. Again, the proportions in general were higher among participants who worked at PAH‐specialized centers.

3.3. Factors Associated With the Decision to Choose Parenteral Infusion Therapy, Dual or More Combination Therapy, and Triple or More Combination Therapy

Tables 4, 5, 6 summarized the results of logistic regression analysis, where factors associated with the decision to choose parenteral infusion therapy, dual or more combination therapy, and triple or more combination therapy, were examined. Six participants who reported they used other supportive therapy or calcium channel blockers only or no pharmacotherapy were excluded from the regression analysis for dual and triple combination therapies.

Table 4.

A logistic regression model examining participants' characteristics associated with experience in the use of parenteral infusion therapy for PAH (n = 400).

	Never used parenteral infusion therapy		Have used parenteral infusion therapy		Adjusted odds ratio of having ever used parenteral infusion therapy
	n	%	n	%	aOR	95% CI	p value
TOTAL	166	100	234	100
PAH‐specialized center
No	130	78.3	122	52.1	Reference
Yes	36	21.7	112	47.9	2.6	1.5–4.3	< 0.001
The number of PAH patients treated over the past 5 years
1–9	143	86.1	127	54.3	Reference
10 or more	23	13.9	107	45.7	2.0	1.1–3.7	0.03
Frequency of treating PAH patients
Occasionally	20	12.0	15	6.4	Reference
Regularly	146	88.0	219	93.6	1.1	0.5–2.4	0.89
Experience of treating high‐risk PAH patients
No	108	65.1	51	21.8	Reference
Yes	58	34.9	183	78.2	3.5	1.8–6.6	< 0.001
Experience of treating PAH patients with a mean initial mPAP of 31–40 mmHg
No	75	45.2	35	15.0	Reference
Yes	91	54.8	199	85.0	1.7	1.0–3.2	0.07
Experience of treating patients with a mean initial mPAP of 41–50 mmHg
No	112	67.5	74	31.6	Reference
Yes	54	32.5	160	68.4	1.5	0.8‐3.0	0.21
Experience of treating patients with a mean initial mPAP of 51 mmHg or higher
No	128	77.1	139	59.4	Reference
Yes	38	22.9	95	40.6	0.8	0.4–1.4	0.28
Experience of treating patients with comorbidities
No	98	59.0	145	62.0	Reference
Yes	68	41.0	89	38.0	1.8	1.1–2.9	< 0.001
Availability of collaboration with other departments or facilities
“Rarely” or “never”	53	31.9	47	20.1	Reference
“Frequently” or “always”	113	68.1	187	79.9	1.5	0.9–2.5	0.17

Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; mPAP, mean Pulmonary Artery Pressure; PAH, Pulmonary Arterial Hypertension.

Table 5.

A logistical regression model examining participants’ characteristics associated with experience of prescribing dual or higher combination therapy for PAH (n = 394). ^a

	Monotherapy		Dual (or higher) therapy		Adjusted odds ratio of choosing dual (or higher) therapy
	n	%	n	%	aOR	95% CI	p value
TOTAL	79	100	315	100
PAH‐specialized center
No	67	84.8	180	57.1	Reference
Yes	12	15.2	135	42.9	3.0	1.4–6.5	0.01
The number of patients with PAH treated over the past 5 years
1–9	77	97.5	187	59.4	Reference
10 or more	2	2.5	128	40.6	4.0	0.9–18.7	0.08
Frequency of treating PAH patients
Occasionally	13	16.5	17	5.4	Reference
Regularly	66	83.5	298	94.6	2.4	0.9–6.1	0.08
Experience of treating high‐risk patients
No	69	87.3	83	26.7	Reference
Yes	10	12.7	231	73.3	5.9	2.5–14.2	< 0.001
Experience of treating patients with a mean initial mPAP of 31–40 mmHg
No	47	59.5	58	18.4	reference
Yes	32	40.5	257	81.6	1.6	0.8–3.1	0.15
Experience of treating patients with a mean initial mPAP of 41–50 mmHg
No	68	86.1	112	35.6	reference
Yes	11	13.9	203	64.4	2.6	1.1–6.6	0.04
Experience of treating patients with a mean initial mPAP of 51 mmHg or higher
No	70	88.6	191	60.6	Reference
Yes	9	11.4	124	39.4	0.9	0.3–2.3	0.77
Experience of treating patients with comorbidities
No	49	62.0	102	32.4	Reference
Yes	30	38.0	213	67.6	0.4	0.2–0.7	< 0.001
Availability of collaboration with other departments or facilities
“Rarely” or “never”	25	31.6	72	22.9	Reference
“Frequently” or “always”	54	68.4	243	77.1	1.0	0.5–2.1	0.93

Abbreviations: aOR, Adjusted odds ratio; CI, confidence interval; mPAP, mean Pulmonary Artery Pressure.

^a Those who have responded they have never provided pharmacotherapy, and who have only provided supportive therapy or calcium channel blockers.

Table 6.

A logistical regression model examining participants’ characteristics associated with experience of prescribing triple or higher combination therapy for PAH (n = 394). ^a

	Monotherapy		Triple (or higher) therapy				Adjusted odds ratio of choosing triple (or higher) therapy
	n	%	n		%		aOR				95% CI				p value
TOTAL	158	100	236		100
PAH‐specialized center
No	127	80.4	120		50.9	Reference
Yes	31	19.6	116		49.2	2.7				1.5–2.7				< 0.001
The number of PAH patients treated over the past 5 years
1–9	150	95.0	114		48.3	Reference
10 or more	8	5.1	122		51.7	7.4				3.2–16.8				< 0.001
Frequency of treating PAH patients
Occasionally	23	14.6	7		3.0	Reference
Regularly	135	85.4	229		97.0	3.3				1.3–8.9				0.02
Experience of treating high‐risk PAH patients
No	108	68.4	45		19.1	Reference
Yes	50	31.7	191		80.9	3.4				1.7–6.7				< 0.001
Experience of treating patients with a mean initial mPAP of 31–40 mmHg
No	73	46.2	32		13.6	Reference
Yes	85	53.8	204		86.4	1.5				0.8–2.8				0.23
Experience of treating patients with a mean initial mPAP of 41–50 mmHg
No	109	69.0	71		30.1	Reference
Yes	49	31.0	165		69.9	0.9				0.5–1.9				0.87
Experience of treating patients with a mean initial mPAP of 51 mmHg or higher
No	133	84.2	128		54.2	Reference
Yes	25	15.8	108		45.8	1.6				0.8–3.2				0.15
Experience of treating patients with comorbidities
No	80	49.4	163		69.1	Reference
Yes	78	51.7	73		30.9	0.8				0.4–1.3				0.33
Availability of collaboration with other departments or facilities
“Rarely” or “never”	50	30.9	47		19.9	Reference
“Frequently” or “always”	108	69.1	189		80.1	1.7				0.9–3.0				0.10

Abbreviations: aOR, Adjusted odds ratio; CI, confidence interval; mPAP, mean Pulmonary Artery Pressure.

^a Those who have responded they have never provided pharmacotherapy, and who have only provided supportive therapy or calcium channel blockers.

Out of a total of 400 participants, 58.5% (n = 234) reported having ever used parenteral infusion therapy, while 41.5% (n = 166) had never used them. Factors associated with the use of parenteral infusion therapies were working in PAH‐specialized center (aOR 2.6, 95% CI: 1.5–4.3, p < 0.001), experience of treating high‐risk patients (aOR 3.5, 95% CI: 1.8–6.6) and having experience of treating PAH patients with comorbidities (aOR 1.8, 95% CI: 1.1–2.9, p < 0.001). Having treated 10 or more patients in the past 5 years (aOR 2.0, 95% CI: 1.1–3.7, p = 0.03) was also associated with the use of parenteral infusion therapies (Table 4).

With regards to the use of dual or higher therapy compared to monotherapy, out of the total respondents, 79.9% (n = 315) reported ever using dual or higher combination therapy. Factors associated with the use of dual or higher combination therapy were experience of treating high‐risk patients (aOR 5.9, 95% CI: 2.5–14.2, p < 0.001). Furthermore, working in PAH‐specialized centers (aOR 3.0, 95% CI: 1.4–6.5, p = 0.01) and experience of treating patients whose initial mPAP was 41–50 mmHg (aOR 2.6, 95% CI: 1.1–6.6, p = 0.04) were also significantly associated with ever using dual or higher combination therapy (Table 5).

With regards to the use of triple or higher therapy compared to monotherapy, among the 394 respondents, 59.9% (n = 236) reported using triple or higher therapy. Factors associated with the use of triple or higher therapy were working in PAH‐specialized centers (aOR 2.7, 95% CI: 1.5–2.7, p < 0.001), seeing 10 or more patients in the past 5 years (aOR 7.4, 95% CI: 3.2–16.8, p < 0.001) and experience of treating high‐risk patients (aOR 3.4, 95% CI: 1.7–6.7, p＜0.001). Regularly seeing patients was also associated with ever using tripe or higher therapy (aOR 3.3, 95% CI: 1.3–8.9, p = 0.02) (Table 6).

4. Discussion

Our study sought to describe the most recent landscape of treatment and management of PAH patients among PAH‐specialized and non‐PAH‐specialized centers in Japan. In total, 37.0% (n = 148) of the participants to our study currently worked at a PAH‐specialized center, the proportion of which was less than that reported in an international survey conducted in 2012, whereby out of 69 respondents from Japan, 43.5% (n = 30) had worked at PAH‐specialized treatment center [24]. The difference may partially be explained by our study intentionally recruiting physicians from outside cardiology and pulmonology departments, so as to capture as wide a picture of clinical practice as possible in Japan. Furthermore, working at a PAH‐specialized center alone may not have indicated the participant having the up‐to‐date skills and knowledge and the experience of treating PAH, however, in our study, those working at PAH‐specialized center did tend to have experience treating greater number of PAH patients and hence more experience. Interestingly, the frequency of following‐up patients was similar if not only slightly higher among those working at a PAH‐specialized center (e.g., 95.3% vs. 88.9%) (Table 2).

Notably, 68% and 35.3% of participants reported treating CTD‐PAH and CHD‐PAH patients, respectively (Table 2), in the current study, figures that differ from those reported in the previous study [14]. CTD‐PAH is typically diagnosed among elderly population [25], therefore, the higher figure than previous one may partially be a reflection of the aging of patients. Indeed, the proportion of CTD‐PAH in Japan increased significantly from 24.7% during 2008 and 2015 to 32.4% during 2016 and 2020, while the prevalence of other PH etiologies, such as CHD‐PAH and PoPH, remained stable or declined during the same period [14]. CHD‐PAH is relatively common in Asia population [26]. For instance, national registry studies in China have reported that approximately 45% of patients with PAH are diagnosed with adult CHD‐PAH [27, 28]. On the other hand, CHD‐PAH is often congenital in nature and may initially be diagnosed and managed by pediatric cardiologists. In China, the absence of an implemented newborn screening program of CHD prior to 2018 may lead to the delay of diagnosis and management, thus resulting in the high prevalence of adult CHD‐PAH [28]. In contrast, early diagnosis and treatment initiation may help prevent the development of PAH and ultimately contribute to decline in CHD‐PAH proportion [29] observed in Japan over the past few decades [14]. In the current study, as for the unexpectedly high proportion of physicians reporting experience of treating CHD‐PAH in both PAH‐specialized and non‐PAH‐specialized centers, this may in part have resulted in the inclusion of physicians from a broader range of departments, including pediatric. These descriptive perspectives on clinician‐level experiences and patient‐level composition underscore the importance of additional research to understand where this misalignment originates.

We also observed that the proportion of physicians reporting experience with each PAH subtype was substantially higher in PAH‐specialized centers compared to non‐PAH‐specialized centers. This difference was particularly notable for HPAH (41.2% vs. 9.9%). This may be because HPAH is genetically determined, with genetic testing typically available only at PAH‐specialized centers, suggesting an importance of cooperation between PAH‐specialized and non‐PAH‐specialized facilities to ensure appropriate diagnosis and care. Although more physicians in PAH‐specialized centers reported experience treating patients with comorbidities, high‐risk profiles, or elevated initial mPAP, the differences compared to non‐PAH‐specialized centers were modest (Table 2). This suggests that a substantial number of high‐risk PAH patients are managed outside PAH‐specialized centers, potentially reflecting limited access or insufficient collaboration between institutions.

Another notable finding of the current study is the relatively high prescription rates of oral prostacyclin in both PAH‐specialized and non‐specialized settings. Although parenteral infusion and inhalant prostacyclin was prescribed less frequently, 19.4% of physicians in non‐PAH‐specialized centers reported use of this type of treatment, which remains comparatively high. In Japan, registry data suggest that oral prostacyclin agents (e.g., selexipag) are widely used across disease severities, whereas parenteral therapy is more selectively reserved for advanced disease [30]. These differences may reflect country‐specific clinical practices, including greater drug availability, historical adoption of oral prostacyclin, and a preference for less invasive treatment options given the complexity and treatment burden associated with parenteral therapies. Accordingly, the relatively high use of oral prostacyclin may represent a characteristic feature of PAH management in Japan and warrants further comparative evaluation across different healthcare settings.

In contrast, the proportions of physicians who reported prescribing dual, triple, or higher‐order combination therapies were low. This finding is consistent with prior real‐world studies demonstrating underutilization of intensive treatment strategies despite current guideline recommendations [14]. This apparent discrepancy between the high use of prostacyclin and the low adoption of combination therapies may be partly explained by the broad categorization of oral prostacyclin in this study, which likely includes agents such as beraprost that are historically used across a wide range of disease severities in Japan. Accordingly, prostacyclin use may not necessarily reflect its incorporation into guideline‐recommended combination strategies and instead suggest that such agents are often introduced without sufficient optimization of background therapies. This may reflect a tendency to add therapies sequentially, rather than introducing combination therapy early as recommended in current guidelines.

The results from the logistic regression analyses indicated that working at PAH‐ specialized centers, and participants' personal experience of treating PAH patients, especially of treating high‐risk patients who require combination therapies, were independently associated with the prescribing of triple therapies. Though not statistically significant, a similar trend was also observed for dual therapies. This finding is in part consistent with results from previous studies [24, 30], which have indicated that physicians working at non‐PAH‐specialized centers may more likely encounter institutional and logistical barriers to initiation of complex treatment regimens, such as the rate of drug inventory in the hospital. On the other hand, our findings also indicate that continued underutilization of intensive treatment regimens may not be an issue solely among non‐PAH‐specialized centers.

A previous study based on the JAPHR database investigating the reasons for not prescribing initial combination therapy including intravenous PGI2 in patients with severe PAH found that those who received initial triple therapy including PGI2 had higher mPAP compared to those who received initial triple therapy with two or more drugs excluding PGI2 [31]. However, our study showed that higher mPAP was not necessarily a consistent factor associated with the use of combination therapy or parenteral infusion therapies. It should be noted, however, that the “initial mPAP” level reported in the current study may not represent the true baseline mPAP, as some patients may have been diagnosed and began their treatment elsewhere before being referred to physicians who took part in this study.

Our results also revealed that experience in treating high‐risk patients was significantly associated with the use of parenteral infusion therapies and the adoption of dual or triple combination therapies. These findings suggest that physicians are more likely to intensify treatment for high‐risk patients, which is, to some extent, consistent with the Japanese treatment guidelines [10]. Furthermore, previous studies have also reported that combination therapy is generally preferred for patients with severe PAH, either stratified according to the French risk assessment criteria or based on physicians' clinical judgment [14, 32]. However in the current study, the evaluation of “high risk” relied solely on physicians' clinical assessment, as standardized risk assessment criteria were not yet incorporated into the Japanese guidelines at the time of the study. Notably, the latest Japanese guidelines, updated in March 2025, have now formally included risk assessment criteria, which allow for more precise stratification of PAH patients based on prognosis.

Given the need for careful consideration when initiating combination therapy in PAH patients—due to safety concerns, comorbidities, and potential drug interactions, we hypothesized that physicians with greater experience in managing comorbidities would be less likely to actively choose dual therapy. However, such a trend was not necessarily indicated by our study results. We were unable to determine the reasons for the inconsistency in our results, however, again, the interpretation may be limited to since physicians were asked their experience in ever treating patients with comorbidities, but when the comorbidities were diagnosed, that is, pre or post‐initiation of PAH treatment, was unknown. Taken all together, our findings suggest that, contrary to the initial hypothesis, the factors influencing the choice of combination therapy may not be singular but rather multifaceted. In particular, we thought factors such as the complexity of patient background, physicians' perception of treatment safety, institutional framework, and physicians' treatment experience as potential influences on the implementation of combination therapy. While this study has identified some of these factors, it has not captured all the multifaceted elements that influence decisions on combination therapy. Future research should comprehensively examine the clinical, psychological, and social factors involved in treatment selection through more multifactorial studies.

This study did not assess referral patterns between PAH‐specialized and non‐PAH‐specialized centers. Accordingly, it remains unclear whether physicians in non‐specialized settings refer patients with severe disease or those requiring complex therapies, such as parenteral prostacyclin, to specialized centers. Although some high‐risk patients appear to be managed outside specialized centers, these findings should be interpreted with caution, as prior referrals or shared‐care arrangements cannot be determined from the current data.

The findings of this study have several important implications for clinical practice. First, greater clarity is needed to support broader dissemination and implementation of guideline‐based treatments, particularly in non–PAH‐specialized centers. Not all, but at least some patients in non‐PAH‐specialized centers are at intermediate and high risks. Considering that PAH is a progressive disease, it appears that a certain proportion of intermediate/high‐risk patients are being treated by physicians at non‐specialized centers and are, in reality, not receiving sufficient treatment intensification through combination therapy. Therefore, the importance of medical education activities aimed at the appropriate dissemination of the guidelines is of interest. Second, improving access to multidisciplinary support—such as structured referral pathways between PAH‐specialized and non–PAH‐specialized centers or collaborative care models—could facilitate the timely and appropriate escalation of therapy. Given the low hospital inventory rates of parenteral prostacyclin in non–PAH‐specialized centers, this suggests that physicians face difficulties in intensifying treatment due to institutional constraints. Third, although risk stratification is a critical component of treatment decision‐making, it remains underutilized. Promoting the use of standardized prognostic assessment tools may help ensure that high‐risk patients receive appropriately aggressive therapy, regardless of provider specialty or facility type. Finally, there is an opportunity to leverage digital tools and clinical decision‐support systems to assist physicians in selecting optimal therapies based on patient risk profiles, comorbidities, and institutional resources. This may be particularly beneficial for physicians who infrequently manage PAH patients but are nonetheless responsible for initiating or adjusting treatment plans.

4.1. Limitations

Firstly, while the study participants were recruited from a large and diverse clinical settings, selection bias may exist given the recruitment via a commercial panel. Thus, physicians with higher motivation for treating PAH patients and better internet access may more likely have participated in the survey. Secondly, to incorporate perspectives from a broader range of specialties—including dermatology and pediatrics—quota was set up for the number of target recruitments from each specialty, meaning the distribution of specialty of our study population is not necessarily the reflection of the real‐world settings. Thirdly, PAH‐specialized centers in this study were defined based on the updated version of the list published by the JPCPHS, with additional inclusion of lung transplantation center. This approach reflects a definition more aligned with real‐world clinical practice and may differ from definitions used in previous studies [21]. Furthermore, the study did not assess patient‐level outcomes or verify actual prescriptions using administrative data, which could have strengthened the interpretation of the findings. Furthermore, this study did not collect information on referral pathways or the timing of patient transfers between institutions. As a result, we were unable to determine whether treatment decisions were made at the initial point of care or after referral to a specialized center. This limitation restricts our ability to fully interpret differences in treatment patterns across settings. In addition, our cross‐sectional design limits causal inferences; longitudinal or mixed‐method approaches may offer deeper insights into evolving treatment patterns.

5. Conclusions

This study underscores notable discrepancies between guideline‐recommended management of PAH and real‐world clinical practice in Japan. While oral therapies were widely implemented, the utilization of parenteral infusion therapies and advanced combination regimens remains suboptimal, particularly in non‐PAH‐specialized centers. Bridging these gaps will require targeted physician's education, strengthened interdepartmental and inter‐facility collaboration, and enhanced systemic support. Such efforts have the potential to improve both the quality of care and clinical outcomes for patients with PAH. Further investigation is warranted to identify patient‐level barriers and to assess effective strategies for promoting adherence to clinical guidelines across diverse healthcare environments.

Author Contributions

Yoko Arai provided overall supervision of the study design, including the development of the questionnaire. Wen Zhang was responsible for the conceptualization and design of the study. The initial draft of the manuscript was prepared by Wen Zhang and Shohei Yamauchi, with substantial critical revisions contributed by Yoko Arai, Shunta Akutsu, and Shigeru Tokita. All authors participated in the analysis and interpretation of the data, contributed significantly to the critical review and revision of the manuscript, and approved the final version for submission.

Shunta Akutsu is the guarantor of this study and takes full responsibility for the overall content, including the integrity of the data and the accuracy of the data analysis, and oversaw the final revision and submission of the manuscript.

Ethics Statement

The study protocol was approved by the Institutional Review Board of Public Health Research Foundation on 22 July 2024 (reference number: 24F0005).

Conflicts of Interest

S.A., S.T., and Y.A. are employees of MSD K.K., Tokyo, Japan, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA, a pharmaceutical company which markets medications for the treatment of PAH. S.Y. and W.Z. are employees of IQVIA Solutions Japan G.K., a consultancy company who received funding from MSD K.K., Tokyo, Japan for the implementation of this study.

Data Availability Statement

Research data are not shared due to consent issues.