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INTRODUCTION
Pulmonary arterial hypertension (PAH) is a rare and chronic disease that affects the small blood vessels in the lungs. Before 2000, it was considered an incurable disease with no effective treatments available. However, the development of targeted therapy for PAH has sparked increased interest in the field and led to advancements in diagnosis and treatment.1)2) This progress primarily began in Western countries,3)4)5) where awareness of the disease and the development of targeted therapies started earlier and spread worldwide.
PAH etiology displays regional variations, with a higher prevalence of congenital heart disease (CHD) in Asian countries in contrast to Western counterparts. The distribution of connective tissue disease (CTD) also differs.6)7)8) This heterogeneity extends to the availability and timing of PAH medications, consequently influencing survival rates and treatment strategies, which diverge between Western and Asian nations.
Because of the relatively low prevalence of PAH, it has become essential to establish and analyze PAH registries in order to gain a better understanding of the disease’s epidemiology and clinical progression. In Korea, a multicenter PAH registry was conducted from 2008 to 2011.9)10) Nonetheless, this registry encompassed patients with potential diagnostic challenges, including a low rate of diagnoses confirmed through right heart catheterization (RHC), and it had limited follow-up data.
It has been fifteen years since targeted therapy for PAH became available in our country.11)12) Therefore, based on the largest single-center PAH registry in Korea, our aim is to describe the demographics, clinical and hemodynamic parameters of PAH patients, and evaluate potential differences in treatment patterns and survival rates in PAH following the introduction of targeted therapy.
METHODS
Ethical statement
The study protocol was approved and the requirement for written informed consent of individual patients was waived or acquired depending on diagnostic periods by the Institutional Review Board (IRB) of Samsung Medical Center. This study was conducted according to the principles of the latest version of the Declaration of Helsinki (2013). (IRB No. 2012-02-079).
Study population
The Samsung Medical Center Pulmonary Arterial Hypertension (SMC PAH) registry is a single-center, prospective, observational cohort encompassing patients with newly diagnosed or pre-existing PAH (World Health Organization [WHO] classification Group 1 pulmonary hypertension). This registry is conducted at a tertiary university hospital with a capacity of 2,200 in-hospital beds. The study comprised 230 patients diagnosed and/or treated at the pulmonary hypertension clinic, within the Division of Cardiology, spanning from March 1999 to November 2021. The diagnosis was established in the pulmonary hypertension clinic through a comprehensive approach involving echocardiography, pulmonary function tests, laboratory analyses, chest computed tomography, lung ventilation/perfusion scans, and RHC when applicable. While RHC was generally performed, cases where it was avoided due to patient preference or medical contraindications were diagnosed based on severe pulmonary hypertension criteria (tricuspid regurgitation velocity >3.4 m/s), along with conclusive right heart changes in echocardiography, and after excluding other potential causes of pulmonary hypertension while associated diseases like CHD or CTD were present. Patients with single-visit consultations seeking a second opinion were excluded from the study.
Clinical variables and definitions
The registry collected baseline demographics, clinical, and hemodynamic parameters during the initial assessment at enrollment. Subsequent follow-up visits updated clinical and medication data. The study analyzed variables including age, gender, dates of symptom onset, diagnosis, and treatment initiation, family history of PAH, PAH etiology, symptoms and signs of right ventricular failure, laboratory findings (including serum N-terminal pro-brain natriuretic peptide [NT-proBNP] levels), 6-minute walk distance, echocardiographic measurements, and RHC hemodynamic measurements.
The SMC PAH registry also tracked longitudinal PAH treatment data. PAH-targeted drugs were defined as medications affecting endothelin-1, prostacyclin, and nitric oxide pathways. Endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors, soluble guanylate cyclase analogues, and prostacyclin pathway medication (prostacyclin analogues and selective prostacyclin receptor [IP3R] antagonists) were included. Excluded from this definition was short-acting beraprost, a prostacyclin analogue with limited long-term data and diminishing use. Combination therapy entailed concurrent prescription of 2 or more PAH-targeted drugs, while patients on none of these medications received conventional therapy.
Events were tracked including all-cause death, lung transplantation, and loss to follow-up. Survival analysis covered all-cause death, with patients undergoing lung transplantation, not deceased, or lost to follow-up being censored at their last documented visit.
Comparison analysis before/after 2007
The landscape of PAH treatment shifted notably after 2007 with the widespread availability of targeted therapy. A comparative analysis was conducted to evaluate changes in clinical variables and the utilization of targeted therapy between patient groups diagnosed before and after 2007.
However, when it came to comparing survival rates, the limited number of patients enrolled before 2007 and significant disparities in patient characteristics made a direct survival comparison impractical. In this approach, an additional 50 patients diagnosed between 1994 and 2006, not initially part of the SMC PAH registry, were retrospectively included as a historical group through electronic medical record review. It is noteworthy that a substantial portion of the historical group patients had received follow-up care in respiratory medicine or pediatrics.
Statistical analysis
The normality assumption was verified using the Shapiro-Wilk test. Categorical variables are reported as the number and relative frequency (%) and were compared using the χ2 test or Fisher’s exact test. Continuous variables were assessed using 2 sample t-test or the Wilcoxon rank sum test, and data are presented as means ± standard deviations or median and interquartile range. No imputation methods were used to infer missing values of baseline variables.
Kaplan-Meier analyses were performed for survival analysis and results were presented as survival rates with 95% confidence intervals (CIs). Treatment effects were estimated by Cox proportional hazard regression models and results are presented as hazard ratios (HRs) with 95% CIs. Multivariable Cox regression analyses were also done, adjusting age, sex, and etiology of PAH (idiopathic PAH, CTD-PAH, CHD-PAH). For comparative survival analysis, we truncated the follow-up time to 15 years, to calibrate differences of the follow-up period according to the time of diagnosis. Before evaluating whether there was a difference in survival based on the diagnosis date or initial treatment, the age and sex were matched. Baseline characteristics of the matched population based on the diagnosis date and initial treatment were analyzed (Supplementary Tables 1 and 2). Multivariate Cox regression model and log-rank tests were used to compare survival.
All probability values were 2-sided, and p values <0.05 were considered statistically significant. Data were analyzed by using SAS software, version 9.4 (SAS Institute Inc., Cary, NC, USA), Rex package (Rex: Excel-based statistical analysis software, version 3.0.3; RexSoft Inc., Seoul, Korea) and R version 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
Population characteristics and comparison before/after 2007
In total, 230 PAH patients from the SMC PAH registry were analyzed (March 1999 to November 2021). Among these, 57 were diagnosed before 2007, and 173 after 2007. Gender distribution (72.6% women) remained consistent across both periods. Patients diagnosed after 2007 were older (mean age 44.8 vs. 27.7 years, p<0.001) and initiated PAH treatment earlier from symptom onset (median 123 vs. 3,469 days, p<0.001) and diagnosis (median 1 vs. 3,464 days, p<0.001) compared to those diagnosed before 2007 (Table 1).
Table 1
Baseline characteristics
Data presented as mean ± standard deviation, median (Q1, Q3), or as number (%).
6MWD = 6-minute walk distance; 6MWT = 6-minute walk test; DLCO = diffusing capacity of the lung of carbon oxide; JVP = jugular venous pressure; mPCWP = mean pulmonary capillary wedge pressure; mPAP = mean pulmonary arterial pressure; mRAP = mean right atrial pressure; NT-proBNP = N-terminal pro-brain natriuretic peptide; PAH = pulmonary arterial hypertension; PVR = pulmonary vascular resistance; RHC = right heart catheterization; SvO2 = saturation of mixed venous oxygen; TAPSE = tricuspid annular plane systolic excursion measured by echocardiography; WHO = World Health Organization.
In the overall cohort, the majority had CHD-associated PAH (CHD-PAH) at 43.0%, followed by CTD-associated PAH (CTD-PAH) at 29.6%, and IPAH at 19.1%. Prior to 2007, 78.9% had CHD-PAH, while only 12.3% and 8.8% had CTD-PAH and IPAH, respectively. Post-2007, CHD-PAH proportion decreased to 31.2%, with CTD-PAH and IPAH proportions rising to 35.3% and 22.5%, respectively (Table 1, Figure 1). Among CHD-PAH patients, atrial septal defect (ASD) constituted the largest subset (48.5%), followed by ventricular septal defect (21.2%) and persistent ductus arteriosus (18.2%). Notably, systemic lupus erythematosus (SLE) was the most common condition among CTD-PAH patients.
Figure 1
Composition of etiology in total population, patients who were diagnosed before 2007 and after 2007. CHD-PAH proportion decreased from 78.9% to 31.2%, with CTD-PAH and idiopathic PAH proportions rising from 12.3% to 35.3%, 8.8% to 22.5%, respectively.
CHD = congenital heart disease; CTD = connective tissue disease; PAH = pulmonary arterial hypertension.
Among a total of 99 CHD-PAH patients in the SMC PAH registry, 11 patients (11.1%) underwent correction surgery. Half of them underwent ASD closure, 2 patients underwent VSD closure, and another 2 patients underwent PDA closure. There was one case of partial anomalous pulmonary venous connection repair. 10 patients had remained or newly developed PAH after defect correction, and one patient had remained systemic to pulmonary shunt.
Among patients in the SMC PAH registry, 50.5% exhibited World Health Organization functional class (WHO FC) IIII, and 33.5% demonstrated class II at diagnosis. The median NT-proBNP level was 618.4 pg/mL. A 6-minute walk test was performed on 69.8% of patients, with a median distance of 372 m. Approximately 92.2% of patients received their diagnosis through RHC, with a slight increase observed after 2007 (89.5% pre-2007 and 93.1% post-2007, p=0.4). Patients diagnosed pre-2007 exhibited milder symptoms (56.1% of WHO FC II), along with a higher prevalence of hemoptysis and less pericardial effusion. Hemodynamic parameters for those diagnosed pre-2007 indicated elevated mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) compared to patients who were diagnosed after 2007.
Changes of treatment pattern
Table 2 provides an overview of PAH-targeted therapy in the study population. Prior to 2007, over half of the patients received no PAH-targeted drugs, while post-2007, 95% of newly diagnosed patients began PAH-targeted therapy upon diagnosis. Short-acting beraprost was the primary prescription pre-2007, while patients diagnosed after 2007 were more frequently prescribed ERAs and PDE-5 inhibitors, often as initial treatment. Over the follow-up period, the use of ERAs and PDE-5 inhibitors expanded, incorporating new drugs like selexipag and riociguat. Prostacyclin analogues were rarely initiated as initial treatment. The percentage of initial combination therapy remained low across all periods, with double/triple combinations seeing a gradual increase during follow-up, yet still representing less than 30% of the overall population (Figure 2).
Figure 2
Treatment changes between patients who were diagnosed before 2007 and after 2007. The 95% of newly diagnosed patients began PAH-targeted therapy upon diagnosis, after 2007. The proportion of initial combination therapy showed a gradual increase during the F/U period.
F/U = follow-up; PAH = pulmonary arterial hypertension.
Table 2
Trend of treatment change
Data presented as number (%).
IP3R = selective prostacyclin receptor; PAH = pulmonary arterial hypertension; PDE-5 = phosphodiesterase-5; sGC = soluble guanylate cyclase.
Survival analysis
In addition to the SMC PAH registry, 50 patients diagnosed as PAH from 1994 to 2006 but not in the registry were included for the survival analysis. Baseline characteristics of total 280 patients of the survival group were analyzed (Supplementary Table 3), and there was no significant difference in characteristics of age, gender, and composition of etiology compared to the SMC PAH registry.
At a median follow-up duration of 7.9 years, the overall survival rate for the entire follow-up period was 20.0%, and the median survival time was 25.6 years. The overall 1, 3, 5, and 10-year survival rates were 91.3%, 83.7%, 77.4%, and 65.8%, respectively (Figure 3).
Comparing survival rates according to etiology, PAH-CHD showed superior survival rates than other etiologies at 97.5%, 96.7%, and 95.7% for 1, 3 and 5-year survival rates, followed by IPAH (84.6%, 68.5%, 66.5%), and CTD-PAH (87.6%, 74.3%, 55.4%) (log-rank p<0.001) (Figure 4A). Among CHD-PAH patients, Eisenmenger syndrome showed numerically higher survival rates compared with other causes of CHD-PAH (Figure 4B).
To evaluate whether there is a difference in survival rates of PAH patients according to the time period when the point PAH-targeted drugs promptly started, comparative survival analyses were performed. Age and sex were adjusted. In overall survival, diagnosis date did not show a significant survival difference (Figure 5A), however, in the IPAH group, it appeared that patients diagnosed after 2007 had higher survival rates (70.0% vs. 14.6% for 15 years from diagnosis, log-rank p=0.032) (Figure 5B). Considering that some of the patients were already exposed to the PAH-targeted drugs by off-label usage or clinical trials before 2007, a comparative survival analysis based on the initial PAH-targeted treatment was performed. Those who received initial PAH-targeted treatment showed survival benefits more than others (86.8% vs. 59.4% for 15 years from diagnosis, log-rank p=0.006) (Figure 5E). In the IPAH group, a total of 11 patients who started PAH-targeted drugs as initial treatment remained alive until the last follow-up date.
Figure 5
Comparative survival analysis by diagnosis date and initial targeted therapy according to the etiology of PAH. (A-D) Survival curves comparison by patients who diagnosed before/after 2007; (E-H) Survival curves comparison by patients who were treated with initial PAH-targeted therapy vs. conservative treatment. Among the IPAH, CTD-PAH, and CHD-PAH groups of patients, the survival benefit of diagnosis date and initial targeted therapy was the most prominent in the IPAH group.
CHD = congenital heart disease; CTD = connective tissue disease; IPAH = idiopathic pulmonary arterial hypertension; PAH = pulmonary arterial hypertension.
In addition, multivariable Cox regression models were derived to evaluate the prognostic impact of diagnosis date and initial PAH-targeted treatment (Table 3). Initial PAH-targeted therapy tended to have survival benefits in the overall group, without statistical significance (adjusted HR, 0.63, 95% CI, 0.39–1.01, p=0.06). In the IPAH group, both diagnosis date after 2007 and initial PAH-targeted therapy significantly improved prognosis (adjusted HR, 0.24, 95% CI, 0.10–0.55, p<0.001 for diagnosis of 2007, adjusted HR, 0.22, 95% CI, 0.10–0.50, p<0.001 for initial PAH-targeted therapy).
Table 3
Prognostic impact of diagnosis date and initial PAH-targeted treatment according to the etiology of PAH
Values are presented as hazard ratio (95% confidence interval).
CHD-PAH = congenital heart disease-related pulmonary arterial hypertension; CTD-PAH = connective tissue disease-related pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension; PAH = pulmonary arterial hypertension.
*Age, sex, and etiology of PAH (IPAH, CTD-PAH, CHD-PAH) were adjusted for hazard ratio in the overall group. In subgroup analysis, age and sex were adjusted.
DISCUSSION
This study demonstrates the historical changes in the practice patterns of diagnosing and treating PAH at a tertiary referral center in Korea over the last 40 years, which could be applicable to many other Asian countries. The etiology of PAH patients has changed significantly since 2006, when the first Korean Food and Drug Administration-approved PAH targeted therapies (bosentan and iloprost) were introduced in our country. Since 2006, there has been a development of disease awareness campaigns and programs by academic associations, as well as promotional meetings and increased research funding by pharmaceutical companies. These efforts have contributed to the establishment of the Korean PAH registry, despite the limited data collected within a short timeframe.9) As a result, it is not necessarily indicative of a true increase in the incidence of PAH beyond CHD but rather reflects an improvement in diagnostic accuracy. Additionally, the awareness about available treatment methods has led to an increase in referral cases, offering the possibility of improving the clinical course of PAH.
The differences in patient characteristics observed in this study are consistent with findings from other registries, where the age at the time of diagnosis tends to be older in recent years. Raised diagnostic accuracy might have contributed to this finding, as many PAH patients other than IPAH/CHD-PAH are diagnosed. The average diagnostic age of CTD-PAH patients is higher than that of IPAH or CHD-PAH, therefore an increase in the average age of patients has been attributed to the increased diagnosis rate of CTD-PAH patients. In addition, it seems like a considerable number of elderly patients complaining of dyspnea who were regarded as because of other underlying diseases have been diagnosed with PAH along with the increasing disease awareness. A similar pattern was shown in Korea’s health insurance data.11)
Among patients with CHD-PAH, there has been an increase in the proportion of ASD cases. This can be attributed to the wider availability of echocardiography screening compared to earlier years.13) Higher mPAP and PVR in patients diagnosed before 2007 with milder symptoms align with the characteristic profile of CHD-PAH compared to other PAH subtypes.
The prevalence of SLE was higher among patients with CTD-PAH because SLE is more common than systemic sclerosis in East Asian countries, including Korea.10) Moreover, the higher frequency of portopulmonary hypertension could be associated with the elevated incidence of chronic hepatitis B-related liver cirrhosis in Korea.
Notably, all patients diagnosed after 2007 received immediate treatment following diagnosis. In contrast, patients diagnosed before 2007 often faced delays of about 10 years before initiating treatment, primarily due to the medical decision of “no treatment option” for many of them, especially those with CHD-PAH.
The treatment pattern has also undergone changes, both in terms of initial treatment and the follow-up period. Prior to 2006, less than half of the patients received targeted therapy, and such therapy largely comprised short-acting beraprost with low regimen, for which there was limited long-term outcome data. Following the availability of targeted therapies such as bosentan and iloprost (including off-label use of sildenafil) after 2007, a significant shift occurred. Around 95% of patients immediately received targeted PAH therapy upon diagnosis. Although most patients commenced with monotherapy, only a quarter of them transitioned to combination therapy during the follow-up period.
Due to the high cost associated with developing and distributing medications for rare diseases, medical resources, and insurance reimbursement can be restricted in many countries. In Korea, the National Health Insurance system provides coverage for all citizens. However, the policy regarding insurance coverage for PAH has evolved over the past 15 years.14)
Initially, from 2006 to 2014, monotherapy was allowed with restricted indications for more symptomatic patients. In 2014, sequential dual combination therapy became permissible. This expanded to include triple sequential combination therapy in 2016. While treprostinil became available in 2011, epoprostenol remains unavailable as of 2023. Tadalafil is not approved for PAH and is only accessible through off-label usage. Riociguat is available but has never been covered by insurance. Starting in 2022, early combinations were only covered for high-risk patients. As a result, the limited resources allocated for PAH treatment can impact the treatment approach and ultimately influence PAH survival rates when compared to Europe,15)16) U.S.17)18) or Japan.19)20)
In 1984, the National Institutes of Health registry of the United States (US), which was the first to present the data of a large PAH registry, showed 1-, 3-, and 5-year survival rates of PAH patients as 68%, 48%, and 34%.21) However, the development of targeted PAH therapy dramatically improved the survival of the patients. The study from the US (2015–2019) reported that the observed 1-, 2-, and 3-year survival rates in patients with IPAH and heritable PAH were 93%, 83%, and 80% (95% CI, 15–26%), respectively.17) Recent data from the Netherlands (2005–2019) indicated that the median overall transplant-free survival was 6.2 years, with 1-, 3-, and 5-year survival rates of 88%, 71%, and 57%.15)
In Asian countries, a single-center registry from China (1999–2004) reported survival rates for IPAH/FPAH at 1, 2, 3, and 5 years as 68.0%, 56.9%, 38.9%, and 20.8%, respectively.22) A recent multicenter registry from China displayed better survivals at 1, 3, and 5 years, with rates of 95.6%, 87.6%, and 79.2% (77.3–81.2%).23) Japanese multicenter registries (2012–2016) revealed event-free survival rates for IPAH/pulmonary veno-occlusive disease patients at 1, 3, 5, and 10 years as 92.9%, 82.9%, 74.0%, and 59.5%, respectively.19) In Korea, a single-center registry for IPAH (1994–2013, n=71) reported survival rates at 1, 3, 5, and 10 years as 80.1%, 62.0%, 51.5%, and 26.8%,24) similar to China’s single-center registry published in 2007.
Our study, spanning from 1994 to 2021, revealed overall survival rates at 1, 3, 5, and 10 years of 91.3%, 83.7%, 77.4%, and 65.8% for the entire PAH population, and 84.6%, 68.5%, 66.5%, and 52.2% for the IPAH population.
We were primarily interested in examining periodic variations in the survival of PAH patients. Despite the delayed diagnosis and treatment for patients diagnosed prior to 2007, those within that timeframe exhibited better functional class, NT-proBNP levels, and overall survival compared to those diagnosed later. This positive outcome can be attributed to the survivorship bias inherent in cases of CHD-PAH.
Additionally, individuals with CHD-PAH tend to adapt to their constrained lifestyles, which often leads to less pronounced recognition of dyspnea when compared to patients who developed PAH as a new condition during adulthood. In our study group, CHD-PAH demonstrated superior survival rates, consistent with findings from previous research. Eisenmenger syndrome, specifically, displayed better survival rates compared to other causes of CHD-PAH, which aligns with similar observations reported in other studies.25) This is further highlighted by the fact that Eisenmenger syndrome continued to exhibit superior survival rates compared to other causes of CHD-PAH, as noted in other reports.26) Furthermore, 11.1% of CHD-PAH patients in our registry underwent corrective surgery. Although they had residual PAH even after the surgery, those who underwent surgery might have been positively affected by clinical outcomes compared to some patients who were not the candidates to receive correction.
To facilitate a comparison of survival differences linked to the initiation of PAH-targeted therapy, we conducted an age-sex matching analysis. This analysis revealed varying survival curves according to the time of diagnosis, indicating numeric differences related to the accessibility of initial PAH-targeted therapy and the era of higher awareness compared to before. When assessing survival based on initial treatment—specifically, initial PAH targeted therapy vs. conservative treatment—discernible differences in survival over time were evident. Subgroup survival analyses based on initial treatment according to the etiology of PAH were also performed. Among the IPAH, CTD-PAH, and CHD-PAH groups of patients, the survival benefit of initial targeted therapy was the most prominent in the IPAH group with statistical significance.
This study has several limitations. First, this is a single-center study with a limited number of patients compared to the nationwide prevalence of PAH. Also, sample sizes were relatively small after age-sex matching. However, it represents the largest single-center registry and expert center results, thus reflecting the recent changes in clinical practice and outcomes of PAH in the real world. Second, we cannot directly prove differences in survival according to the initial treatment with PAH-targeted medication due to the limited number and duration of follow-up, and we only inferred it through statistical methods. Given the many changes in PAH medication and insurance reimbursement policies since the initial introduction of PAH medication in 2007, further studies may provide insight into real-world outcomes with various treatment strategies in the future.
The introduction of targeted therapy for PAH has led to significant changes in various aspects of PAH management in Korea. The characteristics of newly diagnosed PAH patients, treatment methods, and overall prognosis have all undergone notable transformations. Detection of CTD-PAH cases has shown an increase, and there has been a rise in the utilization of PAH-targeted therapy right from the initial diagnosis. Additionally, there has been an increase in the proportion of patients receiving combination therapy, although this remains limited in its extent.
Importantly, patients who started PAH-targeted therapy as an initial treatment showed higher survival rates than the others. Considering that most patients in the post-introduction of the PAH-targeted therapy era promptly started treatment right away, the shift towards earlier targeted therapy initiation might have likely contributed to the improved survival rates observed among PAH patients in Korea.
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