Abstract
Background
Balloon pulmonary angioplasty (BPA) is recommended for inoperable chronic thromboembolic pulmonary hypertension (CTEPH).
Objectives
The aim of this study was to evaluate the long-term survival benefit of BPA for inoperable CTEPH, especially partial BPA sessions.
Methods
In this multicenter cohort study, 232 patients undergoing BPA (the BPA group) and 70 patients refusing the BPA procedure (the non-BPA group) were enrolled. The BPA group was further divided into the full-BPA group (129 patients) and the partial-BPA group (103 patients). The primary outcome was all-cause mortality.
Results
During a median follow-up time of 6.0 years (Q1-Q3: 3.7-7.3), 17 and 26 patients in the BPA and non-BPA groups died, contributing to 8-year survival rates of 86.7% (95% CI: 80.1%-93.8%) and 57.8% (95% CI: 45.9%-72.8%) in the BPA and non-BPA groups, respectively (P < 0.001, log-rank test). BPA was associated with significantly reduced all-cause mortality in inoperable CTEPH patients (HR: 0.20; 95% CI: 0.12-0.32; P < 0.001). In secondary analysis, the 8-year survival rates were 97.1% (95% CI: 93.8%-99.9%) and 70.0% (95% CI: 55.8%-87.8%) in the full-BPA and partial-BPA groups, respectively, both better than the non-BPA group (P < 0.001, log-rank test). Compared with the non-BPA group, partial BPA was associated with significantly reduced all-cause mortality in inoperable CTEPH patients (HR: 0.38; 95% CI: 0.22-0.70; P = 0.001).
Conclusions
BPA tended to be associated with a reduced risk for all-cause mortality in patients with inoperable CTEPH, even those undergoing partial BPA sessions. These findings are preliminary and must be confirmed in randomized controlled trials.
Key Words: all-cause mortality, balloon pulmonary angioplasty, inoperable chronic thromboembolic pulmonary hypertension, safety
Central Illustration
Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening disease characterized by persistent obstruction of the pulmonary arteries with nonresolving thromboemboli and consecutive pulmonary small-vessel remodeling.1,2 Pulmonary endarterectomy (PEA) has been reported to improve the long-term survival of patients with this lethal disease and has become the standard treatment for CTEPH.3,4 However, about 40% of CTEPH patients are ineligible for surgery because of technical inoperability, comorbidities, or limited access to surgery.5
Thus, the treatment options for patients with inoperable CTEPH have evolved in the past decade, focusing on balloon pulmonary angioplasty (BPA), an endovascular procedure to mechanically dilate stenoses and obstruction of pulmonary arteries,6, 7, 8 and pulmonary arterial hypertension (PAH) medications targeting microvasculopathy.9,10 Recently, results from 2 randomized controlled trials comparing the efficacy of BPA with that of riociguat, the first medical therapy approved for inoperable CTEPH, suggested that BPA might offer greater functional and hemodynamic improvements than medical therapies.11,12
Despite growing evidence in favor of BPA, there is a relative scarcity of long-term survival results of BPA for inoperable CTEPH. In 2017, results from a Japanese registry reported a 3-year survival rate of 94.5% in patients with inoperable CTEPH after BPA.13 The latest 2 international multicenter registries, including patients from Europe, Japan, and the United States, demonstrated 3-year survival rates of 92% and 94.1% in patients with inoperable CTEPH undergoing BPA, respectively.14,15 However, all these survival data were from developed countries, including Europe, Japan, and the United States, where the medical security systems are well developed. Conversely, in developing countries, such as China, the modern BPA strategy was introduced in 2016 but carries a relatively high economic burden to patients, with high cost (about $10,000 per session) and low reimbursement by insurance.16 Although BPA is recommended for patients with inoperable CTEPH, in the real world, some patients refuse it because of high cost or unclear risk-to-benefit ratio. Importantly, some patients decline further BPA procedures after partial BPA sessions with improved cardiac function and exercise capacity because of high economic burden. Thus, evidence of a survival benefit of BPA, especially partial BPA sessions, for patients with inoperable CTEPH in developing countries is limited. In addition, previous registries were single-arm, noncomparative studies, and confounders including medical therapies and baseline characteristics limited the interpretation of survival benefits of BPA.
Therefore, the aim of this study was to evaluate the long-term survival benefit of BPA, including partial BPA sessions, with a contemporary control group, in a multicenter cohort of patients with inoperable CTEPH in China.
Methods
Study population
From January 1, 2016, to December 31, 2024, all consecutive patients with inoperable CTEPH at 3 national pulmonary hypertension referral centers (Fuwai Hospital and Peking Union Medical College Hospital, serving patients mainly from northern China, and Guangdong Provincial People’s Hospital, serving those mainly from southern China) were prospectively enrolled in this cohort study. The diagnosis of CTEPH was made according to established guideline recommendations,1,2 and patients were judged as inoperable according to consensus among the multidisciplinary team at each center, including surgeons experienced in PEA, interventional cardiologist, radiologists experienced in pulmonary vascular imaging, and cardiologists experienced in pulmonary hypertension.
We included patients who underwent BPA (at least 1 BPA session) in the BPA group and those patients who refused BPA in the non-BPA group. Patients who did not initially undergo BPA immediately at diagnosis but underwent the intervention during follow-up were included in the BPA group. For these patients, baseline data collection and the start of follow-up were both defined from the time of the first BPA session. Furthermore, for those patients undergoing BPA procedures, some patients declined further BPA procedures after partial BPA procedures (evaluated by interventional cardiologist as noncompletion of BPA treatment) with improved cardiac function and exercise capacity because of high economic burden. Thus, among the BPA group, patients were further divided into full-BPA and partial-BPA groups in secondary analysis, according to whether BPA procedures were completed. BPA completion was defined when meeting either of the following 2 criteria: 1) nearly normalized pulmonary vascular hemodynamic status (mean pulmonary artery pressure [PAP] <25 mm Hg); and 2) no accessible and clinical meaningful vessels could be further dilated evaluated by interventional cardiologists.
The ethics committees of Fuwai Hospital, Peking Union Medical College Hospital, and Guangdong Provincial People’s Hospital approved the study. Written informed consent was obtained from all patients.
BPA procedures
Similar techniques were used at all 3 centers. The BPA procedure is detailed in the Supplemental Appendix. An interventional strategy of step-by-step dilation guided with a pressure wire and optical coherence tomography was applied to this study.
Medical treatment
Anticoagulation therapy was prescribed for all patients since diagnosis. Although warfarin was recommended as the treatment of choice, novel oral anticoagulant agents were increasingly used in clinical practice given their established efficacy in venous thromboembolism and favorable administration profile compared with warfarin. PAH medications, including endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin derivatives, were prescribed off label on the basis of the judgement of clinical physicians. Riociguat, the only medical therapy approved for CTEPH, has been available in China since July 2018. Its use was guided by physicians’ clinical judgment and patient preference and was substantially limited by its high annual cost in China (approximately $10,000 for riociguat 2.5 mg 3 times daily).
Data collection, outcomes, and definitions
We used occupational titles to divided patients into 3 groups of socioeconomic status (SES) according to the International Standard Classification of Occupations: high (managers and senior specialists such as physicians and teachers), intermediate (specialists, such as office workers, customer service, registered nurses, and social workers), and low (manual workers such as construction workers, cleaning services workers, kitchen workers, and practical nurses).17
Data on patient characteristics at baseline, including demographic information, occupations, medical history, comorbidities, and medical treatments, were collected. Hemodynamic parameters measured by right heart catheterization and other clinical parameters, including World Health Organization (WHO) functional class, 6-minute walk distance (6MWD), and N-terminal pro–brain natriuretic peptide, were collected at baseline and re-evaluation. Regarding the BPA procedure, the numbers of procedures and treated lesions and procedure-related complications were obtained.
Follow-up was performed until February 28, 2025, at regular intervals via clinic visits, phone calls, or online interviews. The primary outcome was all-cause mortality. The secondary outcomes included changes from baseline to re-evaluation in pulmonary vascular resistance (PVR), mean PAP, mean right atrial pressure, cardiac index, WHO functional class, 6MWD, N-terminal pro–brain natriuretic peptide, and oxygen saturation. The safety outcomes were procedure-related complications, including pulmonary artery injury (defined as pooling or extravasation of contrast at the target lesion for BPA caused by wire perforation, balloon overdilation, and high-pressure contrast injection), hemoptysis, lung injury (presence of lung opacities on chest radiography and/or computed tomography with or without hemoptysis, with or without hypoxemia), contrast-induced nephropathy (defined as a peak increase in serum creatinine concentration of either ≥25% or ≥0.5 mg/dL [44.2 μmol/L] over baseline during the first 72 hours postprocedure), allergic reaction to contrast, and periprocedural death (defined as death that occurred within 30 days of the procedure).2
Statistical analysis
The primary analysis was to assess the differences in the primary and secondary outcomes between the BPA group and the non-BPA group, and the secondary analysis was to compare the full-BPA group and the partial-BPA group against the non-BPA group. Survival time was from diagnosis to the date of death or to the censoring date of February 28, 2025. Survival rates were estimated using the Kaplan-Meier method and compared using the log-rank test. Furthermore, 3 Cox regression models were constructed to calculate the unadjusted and adjusted HRs of all-cause death: model 1 included group as the only study variable, model 2 included model 1 plus age and gender, and model 3 included model 2 plus SES, comorbidities, PVR, WHO functional class, anticoagulation treatment, and riociguat treatment. In addition, we conducted 2 sensitivity analyses: 1) an analysis set excluding patients who received warfarin; and 2) an analysis set excluding patients who received riociguat. For all Cox proportional hazards models, we tested the proportional hazards assumption using Schoenfeld residuals. For each model, we examined the correlation between Schoenfeld residuals and survival time, reporting both the global test P value (for the overall model) and the treatment variable test P value. A nonsignificant P value (>0.05) indicates that the proportional hazards assumption is satisfied.
Continuous variables are expressed as mean ± SD and were tested using the independent Student’s t-test or as median (Q1-Q3), tested using the Mann-Whitney U test. Linear mixed-effects models were used to analyze changes in continuous efficacy variables from baseline to re-evaluation. The models included time, treatment group, and their interaction as fixed effects and were adjusted for age and sex. For WHO functional class, a generalized linear mixed model with cumulative logit link and random intercepts was used, adjusted for age and sex. An unstructured covariance matrix was specified to model the correlation between the 2 time points. The primary parameter of interest was the group-by-time interaction, estimating the differential change between groups. Binary variables are expressed as number (percentage) and were tested using the chi-square test.
All statistical analyses were performed using SPSS version 20 (SPSS), and the level of statistical significance was set at P < 0.05.
Results
Study population and baseline characteristics
From January 1, 2016, to December 31, 2024, a total of 302 patients with inoperable CTEPH were included. Among them, 232 patients underwent BPA (the BPA group) and 70 refused BPA (the non-BPA group). Of the 232 patients in the BPA group, 129 patients who completed the BPA procedure were further divided into the full-BPA group, and the remaining 103 patients were divided into the partial-BPA group in secondary analysis (Figure 1). A total of 841 BPA sessions were performed, including 605 sessions in the full-BPA group and 236 in the partial-BPA group. The median number of BPA sessions per patient was 3 (Q1-Q3: 2-5) in the whole BPA group, including 5 (Q1-Q3: 3-6) in the full-BPA group and 2 (Q1-Q3: 2-3) in the partial-BPA group.
Figure 1.
Flowchart
A total of 232 patients in the balloon pulmonary angioplasty (BPA) group and 70 patients in the non-BPA group were included in the primary analysis, and 129 patients in the full-BPA group, 103 patients in the partial-BPA group and 70 patients in the non-BPA group were included in the secondary analysis. CTEPH = chronic thromboembolic pulmonary hypertension; PEA = pulmonary endarterectomy.
Except for more female patients (56.9% vs 42.9%; P = 0.039) and higher SES in the BPA group than the non-BPA group, there were no other significant differences in baseline characteristics and medical therapies between the BPA group and the non-BPA group (Table 1). The full-BPA group had more female patients (61.2% vs 42.9%; P = 0.013), higher mean pulmonary artery wedge pressure (11 ± 3 mm Hg vs 9 ± 3 mm Hg; P = 0.003), and higher SES compared with the non-BPA group, and the partial-BPA group had higher SES compared with the non-BPA group. There were no other significant differences in baseline characteristics and medical therapies (Table 2).
Table 1.
Baseline Characteristics in the BPA Group and Non-BPA Group
| BPA Group (n = 232) |
Non-BPA Group (n = 70) |
P Value | |
|---|---|---|---|
| Age, y | 56 ± 15 | 56 ± 14 | 0.658 |
| Female | 132 (56.9) | 30 (42.9) | 0.039 |
| VTE | 177 (76.3) | 56 (80.0) | 0.517 |
| Recurrent VTE | 20 (8.7) | 11 (15.9) | 0.083 |
| Congenital thrombophilia | 20 (8.6) | 5 (7.1) | 0.694 |
| Antiphospholipid syndrome | 15 (6.5) | 8 (11.4) | 0.170 |
| Comorbidities | 43 (18.5) | 14 (20.0) | 0.794 |
| Coronary heart disease | 19 (8.2) | 4 (5.7) | 0.494 |
| Stroke | 11 (4.7) | 4 (5.7) | 0.988 |
| Renal insufficiency | 16 (6.9) | 4 (5.7) | 0.941 |
| Cancer | 4 (1.7) | 4 (5.7) | 0.162 |
| Anemia | 16 (6.9) | 5 (7.1) | >0.999 |
| Socioeconomic status | <0.001 | ||
| Low | 124 (53.4) | 58 (82.9) | |
| Medium | 84 (36.2) | 12 (17.1) | |
| High | 24 (10.4) | 0 (0) | |
| NT-proBNP, pg/mL | 1,176 (292-2,868) | 1,604 (343-3,059) | 0.775 |
| WHO functional class III/IV | 138 (60.3) | 45 (64.3) | 0.545 |
| 6MWD, m | 396 (320-452) | 366 (285-446) | 0.225 |
| Hemodynamics | |||
| Mean RAP, mm Hg | 8 ± 4 | 8 ± 5 | 0.935 |
| Mean PAP, mm Hg | 47 ± 12 | 47 ± 13 | 0.845 |
| PAWP, mm Hg | 10 ± 4 | 9 ± 3 | 0.115 |
| Cardiac index, L/min/m2 | 2.6 ± 0.9 | 2.5 ± 0.6 | 0.477 |
| PVR, Wood units | 8.8 ± 4.3 | 8.6 ± 4.2 | 0.799 |
| SaO2, % | 90.6 ± 4.9 | 89.9 ± 4.8 | 0.290 |
| SvO2, % | 63.0 ± 8.3 | 62.9 ± 8.2 | 0.882 |
| Medical treatments | |||
| Anticoagulation therapy | 0.791 | ||
| Warfarin | 43 (18.5) | 12 (17.1) | |
| DOACs | 189 (81.5) | 58 (82.9) | |
| PAH medications | |||
| Riociguat | 55 (23.7) | 16 (22.9) | 0.883 |
| None | 8 (3.4) | 6 (8.6) | 0.259 |
| Single | 78 (33.6) | 26 (37.1) | |
| Dual | 126 (54.3) | 31 (44.3) | |
| Triple | 20 (8.6) | 7 (10.0) |
Values are mean ± SD, n (%), or median (Q1-Q3).
6MWD = 6-minute walk distance; BPA = balloon pulmonary angioplasty; DOAC = direct oral anticoagulant agent; NT-proBNP = N-terminal pro–brain natriuretic peptide; PAH = pulmonary artery hypertension; PAP = pulmonary artery pressure; PAWP = pulmonary artery wedged pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure; SaO2 = arterial oxygen saturation; SvO2 = mixed venous oxygen saturation; VTE = venous thromboembolism; WHO = World Health Organization.
Table 2.
Baseline Characteristics in the Full-BPA Group, Partial-BPA Group, and Non-BPA Group
| Full-BPA Group (n = 129) | Partial-BPA Group (n = 103) | Non-BPA Group (n = 70) | P Valuea | P Valueb | |
|---|---|---|---|---|---|
| Age, y | 57 ± 15 | 56 ± 15 | 56 ± 14 | 0.640 | 0.750 |
| Female | 79 (61.2) | 53 (51.5) | 30 (42.9) | 0.013 | 0.266 |
| VTE | 96 (74.4) | 81 (78.6) | 56 (80.0) | 0.376 | 0.829 |
| Recurrent VTE | 10 (7.8) | 10 (9.8) | 11 (15.9) | 0.081 | 0.235 |
| Congenital thrombophilia | 10 (7.8) | 10 (9.7) | 5 (7.1) | 0.876 | 0.556 |
| Antiphospholipid syndrome | 10 (7.8) | 5 (4.9) | 8 (11.4) | 0.388 | 0.107 |
| Comorbidities | 22 (17.1) | 21 (20.4) | 14 (20.0) | 0.606 | 0.950 |
| Coronary heart disease | 8 (6.2) | 11 (10.7) | 4 (5.7) | >0.999 | 0.255 |
| Stroke | 9 (7.0) | 2 (1.9) | 4 (5.7) | 0.965 | 0.364 |
| Renal insufficiency | 8 (6.2) | 8 (7.8) | 4 (5.7) | >0.999 | 0.828 |
| Cancer | 2 (1.6) | 2 (1.9) | 4 (5.7) | 0.228 | 0.364 |
| Anemia | 10 (7.8) | 6 (5.8) | 5 (7.1) | 0.876 | 0.975 |
| Socioeconomic status | <0.001 | 0.047 | |||
| Low | 54 (41.9) | 70 (68.0) | 58 (82.9) | ||
| Medium | 55 (42.6) | 29 (28.1) | 12 (17.1) | ||
| High | 20 (15.5) | 4 (3.9) | 0 (0) | ||
| NT-proBNP, pg/mL | 857 (196-2,605) | 1,958 (567-3,190) | 1,604 (343-3,059) | 0.101 | 0.163 |
| WHO functional class III/IV | 68 (53.5) | 70 (68.6) | 45 (64.3) | 0.145 | 0.552 |
| 6MWD, m | 420 (327-480) | 368 (307-421) | 366 (285-446) | 0.041 | 0.832 |
| Hemodynamics | |||||
| Mean RAP, mm Hg | 8 ± 4 | 8 ± 5 | 8 ± 5 | 0.928 | 0.959 |
| Mean PAP, mm Hg | 46 ± 12 | 49 ± 11 | 47 ± 13 | 0.547 | 0.261 |
| PAWP, mm Hg | 11 ± 3 | 10 ± 4 | 9 ± 3 | 0.003 | 0.143 |
| Cardiac index, L/min/m2 | 2.7 ± 0.7 | 2.6 ± 1.1 | 2.5 ± 0.6 | 0.172 | 0.917 |
| PVR, Wood units | 8.1 ± 4.2 | 9.7 ± 4.3 | 8.6 ± 4.2 | 0.406 | 0.131 |
| SaO2, % | 90.8 ± 4.7 | 90.4 ± 5.0 | 89.9 ± 4.8 | 0.213 | 0.534 |
| SvO2, % | 63.7 ± 8.0 | 62.3 ± 8.6 | 62.9 ± 8.2 | 0.511 | 0.643 |
| Medical treatments | |||||
| Anticoagulation therapy | 0.987 | 0.594 | |||
| Warfarin | 22 (17.1) | 21 (20.4) | 12 (17.1) | ||
| DOACs | 107 (82.9) | 82 (79.6) | 58 (82.9) | ||
| PAH medications | |||||
| Riociguat | 24 (18.6) | 31 (30.1) | 16 (22.9) | 0.475 | 0.293 |
| None | 4 (3.1) | 4 (3.9) | 6 (8.6) | 0.125 | 0.644 |
| Single | 39 (30.2) | 39 (37.9) | 26 (37.1) | ||
| Dual | 77 (59.7) | 49 (47.6) | 31 (44.3) | ||
| Triple | 9 (7.0) | 11 (10.7) | 7 (10.0) |
Values are mean ± SD, n (%), or median (Q1-Q3).
Abbreviations as Table 1.
Comparisons between the full-BPA group and the non-BPA group.
Comparisons between the partial-BPA group and the non-BPA group.
Primary outcome
During the median follow-up time of 6.0 years (Q1-Q3: 3.7-7.3 years), 7 patients were lost to follow-up, including 3 in the BPA group and 4 in the non-BPA group. In the BPA group, 17 patients (7.4%; 95% CI: 4.5%-11.8%) died, including 3 (2.3%; 95% CI: 0.6%-7.2%) in the full-BPA group and 14 (13.9%; 95% CI: 8.1%-22.5%) in the partial-BPA group. In the non-BPA group, 26 patients (39.4%; 95% CI: 27.8%-52.2%). In the full-BPA group, 2 patients died of new-onset cancers, and 1 died of trauma during follow-up. In the partial-BPA group, 2 patients experienced periprocedural death because of severe lung injuries. Nine patients died of aggressive right heart failure during follow-up. One patient had contrast-associated renal dysfunction at his second BPA session and died of renal failure 9 months later. The last 2 patients died of new-onset cancers. In the non-BPA group, 24 patients died of progressive right heart failure, 1 patient died of myocardial infarction, and the last patient died of massive hemoptysis. The timetable of death in different treatment groups is shown in Supplemental Table 1.
In the primary analysis, the 1-, 3-, 5-, and 8-year survival rates were 98.2% (95% CI: 96.5%-99.9%), 97.3% (95% CI: 95.1%-99.4%), 95.0% (95% CI: 92.1%-98.1%), and 86.7% (95% CI: 80.1%-93.8%) in the BPA group, better than the rates of 93.9% (95% CI: 88.4%-99.9%), 77.8% (95% CI: 68.1%-88.8%), 68.9% (95% CI: 58.2%-81.7%), and 57.8% (95% CI: 45.9%-72.8%) in the non-BPA group (P < 0.001, log-rank test) (Figure 2A). Furthermore, the Cox regression analysis (model 3) showed that BPA was associated with a significantly reduced hazard of all-cause mortality in inoperable CTEPH patients (HR: 0.20; 95% CI: 0.12-0.32; P <0.001) (Table 3). Sensitivity analyses showed similar results (Supplemental Tables 2 and 3).
Figure 2.
Survival of Inoperable CTEPH Patients in Different Treatment Groups
(A) Survival rates of inoperable CTEPH patients in the BPA group and the non-BPA group. (B) Survival rates of inoperable CTEPH patients in the full-BPA group, partial-BPA group, and non-BPA group. Dashed lines represent 95% CIs. Abbreviations as in Figure 1.
Table 3.
Cox Regression Models for the Effect of BPA on All-Cause Mortality
| BPA vs Non-BPA |
Full-BPA vs Non-BPA |
Partial-BPA vs Non-BPA |
||||
|---|---|---|---|---|---|---|
| HR (95% CI) | P Values | HR (95% CI) | P Values | HR (95% CI) | P Values | |
| Model 1 | 0.19 (0.10-0.36) | <0.001 | 0.05 (0.02-0.17) | <0.001 | 0.43 (0.22-0.83) | 0.012 |
| Model 2 | 0.19 (0.10-0.36) | <0.001 | 0.05 (0.02-0.17) | <0.001 | 0.43 (0.22-0.83) | 0.012 |
| Model 3 | 0.20 (0.12-0.32) | <0.001 | 0.10 (0.06-0.25) | <0.001 | 0.38 (0.22-0.70) | 0.001 |
Model 1 included group as the only study variable, model 2 was model 1 plus age and gender, and model 3 was model 2 plus socioeconomic status, comorbidities, pulmonary vascular resistance, World Health Organization functional class, anticoagulation treatment, and riociguat treatment.
BPA = balloon pulmonary angioplasty.
In the secondary analysis, the 1-, 3-, 5-, and 8-year survival rates were 100%, 99.2% (95% CI: 97.6%-99.9%), 98.2% (95% CI: 95.8%-99.9%), and 97.1% (95% CI: 93.8%-99.9%) in the full-BPA group and 95.9% (95% CI: 91.9%-99.9%), 94.7% (95% CI: 90.2%-99.3%), 90.5% (95% CI: 84.4%-97.1%), and 70.0% (95% CI: 55.8%-87.8%) in the partial-BPA group, in both cases better than the survival rates in the non-BPA group (P <0.001, log-rank test) (Figure 2B). The Cox regression analysis (model 3) showed that compared with the non-BPA group, full BPA (HR: 0.10; 95% CI: 0.06-0.25; P <0.001) and partial BPA (HR: 0.38; 95% CI: 0.22-0.70; P = 0.001) were both associated with a significantly reduced hazard of all-cause mortality in inoperable CTEPH patients (Table 3). Sensitivity analyses showed similar results (Supplemental Tables 2 and 3). The proportional hazards assumption was satisfied for all Cox models (Supplemental Table 4).
Second outcomes and safety outcomes
Parameters at re-evaluation were not available in 47 patients, including 25 patients in the BPA group and 22 in the non-BPA group. Thus, efficacy analysis was conducted in 207 patients in the BPA group and 48 patients in the non-BPA group. The median duration from baseline to re-evaluation was 9 months (Q1-Q3: 4-19 months) in the BPA group and 12 months (Q1-Q3: 6-24 months) in the non-BPA group (P = 0.155). Detailed information on efficacy analysis is shown in Supplemental Table 5. The adjusted least squares mean difference in PVR between the BPA group and the non-BPA group was −3.7 WU (95% CI: −4.6 to −1.5 WU; P < 0.001). Furthermore, the adjusted odds of patients’ being in WHO functional class III or IV significantly decreased in the BPA group compared with the non-BPA group (OR: 0.18; 95% CI: 0.10-0.39; P < 0.001). Importantly, among 129 patients in the full-BPA group, 18 (14.0%) achieved a mean PAP <20 mm Hg, 64 (49.6%) achieved a mean PAP <25 mm Hg, and 68 (52.7%) discontinued medications approved for CTEPH or PAH. Parameters at baseline and re-evaluation in both groups are shown in Supplemental Table 6. Comparisons of patients with and without complete parameter re-evaluation are displayed in Supplemental Table 7.
Detailed information on BPA procedure-related complications is presented in Supplemental Table 8. BPA procedure–related complications occurred in 143 sessions (17.0%). Severe lung injury occurred in 5 patients within 24 hours after BPA. Among these patients, 3 fully recovered, and the other 2 died despite assistance with extracorporeal membrane oxygenation.
Discussion
In this multicenter cohort study evaluating BPA as a therapeutic intervention for inoperable CTEPH with an extended follow-up duration, we found that BPA had a tendency to be linked with a diminished risk for all-cause mortality, even among those patients undergoing partial BPA sessions (Central Illustration). These results add valuable survival data in favor of BPA for inoperable CTEPH, especially indicating vital survival benefit of partial BPA sessions for patients in developing countries where BPA carries a high economic burden.
Central Illustration.
Long-Term Survival of BPA for Inoperable CTEPH
In a typical patient, balloon pulmonary angioplasty (BPA) improved pulmonary artery perfusion and hemodynamic and functional parameters and normalized cardiac structure. In a multicenter cohort with an extended follow-up period, BPA improved long-term survival rates for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH), even for those undergoing partial BPA sessions. PAP = pulmonary artery pressure; PVR = pulmonary vascular resistance; SvO2 = mixed venous oxygen saturation; WHO = World Health Organization.
Over the past decade, an increasing body of evidence derived from noncomparative studies, predominantly assessing hemodynamic parameters and exercise capacity preprocedure and postprocedure, has indicated that BPA appears to represent an effective therapeutic modality for individuals afflicted with inoperable CTEPH.7,8,14, 15, 16,18,19 However, long-term survival results remain relatively scarce. In 2017, results from a Japanese registry showed a 3-year survival rate of 94.5% in patients with inoperable CTEPH after BPA.13 Recently, 2 international multicenter registries indicated 3-year survival rates of 92% and 94.1% in patients with inoperable CTEPH receiving BPA.14,15 All these registries added valuable survival data for BPA in patients with inoperable CTEPH. Meanwhile, some important profiles are worthy of consideration. First, except for the registry of Delcroix et al14 including patients only receiving medical treatment, which indicated that BPA was associated with a reduced risk for all-cause mortality for patients with inoperable CTEPH, the other 2 registries were single-arm, noncomparative cohort studies, and the majority of study patients also received PAH medications.13,15 It is difficult to rule out the impact of PAH medications on prognosis and to accurately assess the survival benefit of BPA for patients with inoperable CTEPH. Second, participants in these registries were from developed countries, including Europe, Japan, and the United States, with well-developed medical security systems, and most received full sessions of BPA; the mean number of BPA sessions performed for each patient range from 4.6 to 4.9.13, 14, 15 As a result, these registries did not focus on the survival benefit of BPA in those patients who underwent only partial BPA sessions. Conversely, in developing countries such as China, this technique was introduced in 2016 but carries a high economic burden to patients.16 In that case, although BPA is recommended for patients with inoperable CTEPH, in the real world, some patients refuse it or decline further BPA procedures after partial BPA sessions because of high economic burden.
Therefore, to reduce the confounding factors of medical therapies and baseline characteristics in survival analysis, we included a contemporary control group, in which patients refused BPA treatment and received only medical therapy. We revealed that BPA tended to be associated with reduced all-cause mortality in patients with inoperable CTEPH, consistent with the registry of Delcroix et al,14 but with an extended follow-up period (median 6.0 years; Q1-Q3: 3.7-7.3 years). Interestingly, the non-BPA group in our study demonstrated a higher survival rate compared with the previous registry (3-year survival rate 78% vs 71%), despite similar baseline hemodynamic and functional profiles. This survival difference may be attributable partly to the younger age of our cohort (mean 56 years vs 69 years). Moreover, to investigate whether patients who underwent partial BPA sessions could benefit from BPA, we divided patients in the BPA group into full-BPA and partial-BPA groups, and our results indicated that BPA was also associated with reduced all-cause mortality in patients undergoing partial BPA sessions. These results add valuable survival data in favor of BPA for inoperable CTEPH, especially indicating vital survival benefit of partial BPA sessions for patients in developing countries where BPA procedure carries a high economic burden.
When interpreting the survival benefits observed in this study, several important points warrant discussion. First, it is important to emphasize that compared with the partial-BPA group, the full-BPA group was associated with superior long-term survival outcomes, as evidenced by the significant divergence in survival curves in the later follow-up period. Therefore, on the basis of data from this study, the full-BPA strategy also remains the therapeutic goal, if we disregard economic burden and other confounding factors. However, the favorable survival achieved with partial BPA sessions, as highlighted in our study, underscores the need to re-evaluate the traditional criteria for the completion of BPA. Future well-designed research prospectively defining hemodynamic or functional thresholds (eg, a specific reduction in PVR or improvement in 6MWD) that are subsequently validated against the gold standard of long-term survival, even if anatomical completeness is not achieved, is of great clinical importance. This could help optimize the risk/benefit ratio and cost-effectiveness of BPA for individual patient.
Second, a notable observation is that despite presenting with numerically greater baseline severity, patients in the partial-BPA group did not exhibit a significant survival disadvantage compared with those in the full-BPA group during the short-term or mid-term period. The survival curves began to diverge substantially only in the later phases of follow-up. When considering potential reasons, the initial therapeutic response is likely pivotal. Even a limited number of BPA sessions initially can produce significant relative reductions in PVR and right ventricular afterload, especially in patients with high baseline burden. This initial “unloading” effect may yield substantial clinical and survival benefit during the first few years, effectively bridging the survival gap predicted by their baseline severity. Indeed, this further underscores the efficacy of BPA in these patients.
Regarding medical therapy, riociguat remains the only guideline-recommended targeted drug for patients with inoperable CTEPH or persistent pulmonary hypertension after PEA. Recent studies have suggested that BPA may lead to greater improvements in hemodynamic and functional parameters compared with riociguat in this population11,12; however, evidence regarding their comparative effects on long-term survival remains lacking. In China, riociguat was not available until 2018 and has remained costly since its introduction, which may explain why only approximately 23% of patients in our cohort received this treatment. Although we adjusted for riociguat use in our survival analyses, we cannot definitively conclude whether BPA provides a survival benefit over riociguat in inoperable CTEPH. Therefore, further studies directly comparing the long-term survival outcomes of BPA vs riociguat in patients with inoperable CTEPH are of significant clinical importance.
Notably, SES is reported to be associated with mortality in cardiovascular disease, including PAH,20,21 and other potential confounders might limit interpretation of the survival benefit of BPA. To further adjust these confounders, we studied the SES of patients in different treatment group and found that treatment group was independently associated with mortality among inoperable CTEPH patients. However, the role of SES extends beyond a confounding variable to be statistically controlled; it actively shapes the entire clinical pathway. For patients, lower SES may directly limit access to BPA because of financial barriers (eg, procedure costs, lost wages), geographic distance from specialized centers, or health literacy gaps affecting treatment acceptance. For physicians, SES can subtly influence decision-making. In practice, perceived patient affordability may lead to a prioritization of more accessible treatment options or an adjustment of risk/benefit assessments to avoid imposing financial hardship. This introduces a potential selection bias, whereby patients who undergo full-course BPA may represent a socioeconomically advantaged group with distinct baseline risks. Therefore, although our adjusted analysis suggests an independent treatment effect, the generalizability of this benefit across all SES strata requires caution.
Much evidence has indicated that BPA could improve hemodynamic and functional parameters in patients with inoperable CTEPH.7,8,13,18,22, 23, 24, 25 However, these findings have been confounded by concurrent medical therapies in prior studies. To minimize the impact of PAH medications on hemodynamic status and functional parameters, we analyzed the differences in the least squares mean changes of various efficacy parameters between the BPA group and the non-BPA group and obtained the “net efficacy” of the BPA procedure. The results showed that after eliminating the impact of medical therapy, BPA significantly improved hemodynamic and functional parameters in inoperable CTEPH patients, with average decreases of 15 mm Hg in mean PAP and 3.9 Wood units in PVR, which were also consistent with the results of 2 recently published randomized controlled trials11,12 comparing the efficacy of BPA with that of riociguat in patients with inoperable CTEPH, in which patients in the BPA group were medical treatments naive.
Study limitations
First, patients in different treatment groups were not randomized, and the non-BPA group was defined by patients’ refusal of the procedure, introducing potential selection bias. Although baseline hemodynamic status was similar between groups, patients who refused BPA had significantly lower SES and may have differed in unmeasured factors such as health beliefs or frailty. This self-selection limits the group’s validity as a true comparator and may overestimate the observed treatment effect. Despite statistical adjustment for measured confounders, residual confounding cannot be excluded. Therefore, these findings should be considered hypothesis generating and require confirmation in randomized controlled trials.
Second, the substantial proportion of noncardiovascular deaths in the BPA group reduces the statistical power to detect a true difference in disease-specific mortality and may confound the interpretation of survival outcomes.
Third, all 3 centers are pulmonary hypertension referral centers, which represents the top level in the diagnosis and treatment of patients with pulmonary hypertension. Thus, the observed differences may be subject to other possible confounders. Further national registry in China is needed.
Fourth, the small number of patients receiving riociguat precluded any meaningful subgroup analyses to explore its impact on survival outcomes or compare it with BPA in patients with inoperable CTEPH.
Conclusions
BPA tended to be associated with reduced risk for all-cause mortality in patients with inoperable CTEPH, even those undergoing partial BPA sessions. These findings are preliminary and must be confirmed in randomized controlled trials.
Funding Support and Author Disclosures
This study is funded by the National Natural Science Foundation of China (grant 82300082), the Noncommunicable Chronic Diseases–National Science and Technology Major Project (grant 2024ZD0526700), the National Key Research and Development Program of China (grant 2023YFC2509500), and the National Natural Science Foundation of China (grants 82570071, 82170071, and 82300065). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Acknowledgments
The authors express their gratitude to all patients, their families, and the investigators who participated in the study.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
Appendix
For supplemental methods and tables, please see the online version of this paper.
Contributor Information
Kai Sun, Email: sunkaii@gmail.com.
Zhi-Cheng Jing, Email: jingzhicheng@vip.163.com.
Appendix
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