ABSTRACT
We aimed to evaluate the role of medical therapy before and after balloon pulmonary angioplasty (BPA) for non‐operable chronic thromboembolic pulmonary hypertension (CTEPH) in the modern management era. This Japanese nationwide, multicenter, prospective observational registry, including 37 centers, analyzed data newly registered from August 2018–December 2023. Pretreatment before BPA was analyzed in patients who were treatment naïve or received medical therapy only at registration (n = 557). De‐escalation or escalation of medical therapy after BPA was analyzed in patients who underwent BPA (n = 966). The BPA pretreatment analysis in 557 patients showed that approximately 70% of the patients received medical therapy, of which 18% received combination therapy. Patients who received monotherapy or combination therapy had more severe baseline hemodynamics than those who did not. The 3‐year survival did not significantly differ between the no, mono, and combination pretreatment groups (94%, 98%, and 97%, respectively; p = 0.852). The BPA post‐treatment analysis in 966 patients showed that 20% of patients underwent de‐escalation of medical therapy. Patients with de‐escalation of medical therapy had lower mean pulmonary artery pressure (PAP) (20.9 ± 5.8 vs. 24.1 ± 7.3 mmHg, p < 0.01); however, they had a lower cardiac index at last follow‐up compared to patients without de‐escalation (2.66 ± 0.61 vs. 2.84 ± 0.70 L/min/m2, p = 0.01). Patients with severe disease tended to undergo pre‐treatment before BPA; however, patient survival did not differ across pretreatment types. De‐escalation of medical therapy after BPA can affect cardiac index. Therefore, de‐escalation or continuation of medical therapy should be carefully considered even after mean PAP normalizes after BPA.
Keywords: balloon pulmonary angioplasty, Chronic thromboembolic pulmonary hypertension, medical therapy, multimodal therapy, pretreatment
Abbreviations
- BPA
balloon pulmonary angioplasty
- CTEPH
chronic thromboembolic pulmonary hypertension
- NYHA‐FC
New York Heart Association functional class
- PAH
pulmonary arterial hypertension
- PAP
pulmonary arterial pressure
- PEA
pulmonary endarterectomy
- PH
pulmonary hypertension
- PVR
pulmonary vascular resistance
1. Introduction
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by pulmonary artery stenosis and obstruction with non‐resolving organized thromboemboli combined with variable microvasculopathy, leading to elevated pulmonary vascular resistance (PVR), pulmonary hypertension (PH) [1, 2, 3].
Pulmonary endarterectomy (PEA) is the standard treatment for operable CTEPH [4, 5]. Treatment strategies for non‐operable CTEPH have evolved with the availability of balloon pulmonary angioplasty (BPA) [6], in addition to approved or off‐label use of pulmonary arterial hypertension (PAH) medications (prostanoids, endothelin receptor antagonists, and drugs targeting the nitric oxide pathway, i.e., phosphodiesterase type‐5 inhibitors and soluble guanylate cyclase stimulators) [4, 7]. Recently, two randomized controlled trials comparing riociguat and BPA for non‐operable CTEPH have been reported. MRBPA trial (primary endpoint: change in mean pulmonary artery pressure [PAP] at month 12) showed greater improvement in mean PAP among patients treated with BPA; however, patients treated with riociguat showed significantly better improvement in cardiac output [8]. RACE trial (primary endpoint: change in PVR at week 26) showed that PVR reduction by BPA was greater than that by riociguat; however, BPA‐related serious adverse events were fewer in patients who received riociguat pretreatment in the follow‐up study [9]. A multimodal approach combining riociguat and BPA has improved the prognosis of patients with non‐operable CTEPH [7, 10], and multimodal therapy has currently become the standard for non‐operable CTEPH [4, 6, 10]. However, the role of pretreatment of medical therapy before BPA, and the ratio of de‐escalation of medical therapy after BPA remain unclear in the real clinical world. This study aimed to evaluate the role of medical therapy before and after BPA in patients with non‐operable CTEPH in the modern management era using a nationwide multicenter registry.
2. Methods
2.1. Study Design
Patient data were collected from the web‐based CTEPH AC registry, a nationwide, multicenter, prospective, observational registry of patients diagnosed with CTEPH at 37 PH expert institutions across Japan. The CTEPH AC registry complied with the Declaration of Helsinki and was approved by the institutional review board of each institution. The study was registered in the UMIN Clinical Trials Registry, an open‐access database (UMIN 000033784). Patients were diagnosed with CTEPH based on the data of right heart catheterization (mean PAP ≥ 25 mmHg and pulmonary artery wedge pressure ≤ 15 mmHg) and the findings of at least two imaging modalities (ventilation perfusion scan, pulmonary angiography, computed tomography) according to clinical guidelines [11]. Treatment‐naïve patients and those undergoing treatment with PEA, BPA, and/or medical therapy at registration were registered in the CTEPH AC registry. After obtaining written informed consent, each patient was anonymized and assigned a unique patient identification number and registered consecutively. The latest available data up to 12 months before enrollment were collected as baseline data. Follow‐up data and vital status were systematically updated each November by investigators at the participating institutions. In the majority of patients who underwent BPA, follow‐up data were obtained within 1 year after completion of the procedure.
We reviewed the data of all patients diagnosed with CTEPH who were newly registered in the CTEPH AC registry between August 2018 and December 2023. Patients with non‐operable CTEPH who underwent BPA and/or medical therapy were enrolled, and those who underwent PEA were excluded. Patients without follow‐up data were excluded.
2.2. Aim of the Registry
Two major analyses of medical therapy were performed: BPA pretreatment analysis, including patients who were naïve to interventional treatment (neither PEA nor BPA) at registry enrollment, and BPA post‐treatment analyses, including patients who underwent BPA before and/or after registry enrollment.
The primary outcome was the survival between the pretreatment groups. The incidence was defined as all‐cause death and worsening of PH. The secondary outcomes included the hemodynamic and characteristic features before BPA, changes in hemodynamic parameters after BPA in the pretreatment analysis, and clinical features and survival according to continuation or discontinuation of medical therapy after BPA in the post‐treatment analyses. The number of pretreatment drugs was defined as the number of drugs administered at the time of the first BPA session.
2.2.1. Statistical Analysis
All the statistical analyses were performed using GraphPad Prism version 9 (GraphPad Software, La Jolla, CA, USA) and SPSS Statistics 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables are expressed as mean (standard deviation) or median [interquartile range] according to the variable distribution. The primary outcome of survival was analyzed using a log‐rank test with Kaplan‐Meier estimates. For this analysis, the length of survival was determined from the date of diagnostic right heart catheterization at registration to the date of incidence or last visit in patients who were naïve to PEA or BPA at registry enrollment. The cutoff date was December 31, 2023. Patients who were lost to follow‐up were censored at the date of their last confirmed survival.
The secondary outcomes of differences in continuous variables, such as age, 6‐min walk distance, brain natriuretic peptide level, and hemodynamic parameters, were compared using the independent Student's t‐test for normally distributed variables and the Mann–Whitney U test for non‐normally distributed variables. Normality was assessed using the Shapiro‐Wilk test. One‐way analysis of variance (ANOVA) was used to compare multiple groups. Categorical variables, such as gender, New York Heart Association functional class (NYHA‐Fc) and use of medications, were expressed as numbers and percentages and were compared using the χ2 test for independence. Univariate and multivariable logistic regression analyses were used to examine the hemodynamic and characteristic factors associated with the de‐escalation or escalation of medical therapy after BPA. For all analyses, the level of statistical significance was set at p < 0.05.
3. Results
3.1. Balloon Pulmonary Angioplasty Pretreatment Analysis
3.1.1. Patient Population
Between August 2018 and December 2023, 1527 patients diagnosed with CTEPH were newly registered in the web‐based CTEPH AC registry. Of these, 1338 patients had undergone ≥ 1 follow‐up (average 3.1 ± 1.7 times). Of these, 629 patients were treatment naïve or received medical therapy only and had not undergone mechanical intervention (PEA or BPA) at registration. Of these, 151 patients received no treatment or medical therapy at the last follow‐up (No BPA group); 406 patients underwent BPA therapy; 72 patients underwent PEA. We analyzed patients in the No BPA group and patients who underwent BPA therapy (Med 0 to BPA: no pretreatment [n = 111], Med 1 to BPA: pretreatment with monotherapy [n = 242], Med ≥ 2 to BPA: pretreatment with combination medical therapy [n = 53]). The patient cohort of the BPA pretreatment analysis is shown in Figure 1. The baseline characteristics and hemodynamic characteristics of the study population are summarized in Table 1. One‐way ANOVA was used to compare continuous variables between the groups. Patients with pretreatment before BPA had severe hemodynamic or functional profiles, and patients with combination medical therapy tended to have worse hemodynamic and functional statuses. Baseline mean PAP of the Med 1 to BPA group was higher than those of the No BPA group (p = 0.004) and Med 0 to BPA group (p < 0.001), and baseline mean PAP of the Med ≥ 2 to BPA group was higher than those of the No BPA group (p < 0.001) and Med 0 to BPA group (p < 0.001). Baseline cardiac index of the No BPA group was higher than that of the Med 0 to BPA group (p = 0.009). Baseline PVR of the Med 1 to BPA group was higher than that of the No BPA group (p = 0.026), and baseline PVR of the Med ≥ 2 to BPA group was higher than those of the No BPA group (p = 0.003) and Med 0 to BPA group (p = 0.006).
Figure 1.
Patients study cohort of BPA pretreatment analyses (n = 557).
Table 1.
Characteristics and hemodynamics at baseline and at last follow‐up.
| Variable | No Treatment or Med only (n = 151) | Med 0 to BPA (n = 111) | Med 1 to BPA (n = 242) | Med ≥ 2 to BPA (n = 53) | P value** |
|---|---|---|---|---|---|
| Age (years) | 69.4 (12.7) | 68.2 (13.1) | 66.6 (11.9) | 68.0 (12.4) | 0.204 |
| Female (n, %) | 110 (73%) | 76 (68%) | 176 (73%) | 39 (74%) | 0.833 |
| BMI (kg/m2) | 23.1 (4.3) | 23.3 (4.2) | 23.8 (4.6) | 23.2 (4.3) | 0.367 |
| History of cancer (n, %) | 10 (6.6%) | 8 (7.2%) | 18 (7.4%) | 6 (11.3) | 0.731 |
| History of VTE (n, %) | 67 (44.4%) | 47 (42.3%) | 105 (43.4%) | 26 (49.1%) | 0.869 |
| Lung function test | |||||
| % FVC (%) | 93.7 (20.4) | 98.9 (18.4) | 98.6 (16.4) | 96.8 (20.1) | 0.075 |
| % FEV1.0 (%) | 85.9 (17.5) | 88.6 (17.7) | 87.8 (17.1) | 84.9 (14.3) | 0.467 |
| DLCO (%) | 75.8 (22.2) | 71.8 (18.7) | 76.8 (18.0) | 69.0 (23.7) | 0.055 |
| PaO2 (mmHg) | 63.8 (13.5) | 66.9 (13.5) | 60.6 (11.7) | 62.5 (15.2) | 0.002 |
| Anticoagulation | |||||
| VKA (n, %) | 43 (28.5%) | 43 (38.7%) | 58 (24.0%) | 15 (28.3%) | 0.058 |
| DOAC (n, %) | 101 (66.9%) | 68 (61.3%) | 179 (74.0%) | 38 (71.7%) | 0.058 |
| Medical therapy | |||||
| ERA (n, %) | 19 (12.6%) | — | 4 (1.6%) | 18 (34.0%) | |
| PDE5‐I or sGC stimulator (n, %) | 98 (64.9%) | — | 210 (86.8%) | 53 (100.0%) | |
| Prostacyclin receptor agonists (n, %) | 24 (15.9%) | — | 28 (11.6%) | 40 (75.5%) | |
| Baseline characteristics and hemodynamics | |||||
| NYHA‐Fc I/II/III/IV (%) | 5/52/41/2 | 6/45/45/4 | 2/37/58/3 | 0/26/64/10 | < 0.001 |
| 6MWD (m) | 366 (114) | 364 (123) | 351 (103) | 325 (135) | 0.282 |
| BNP (pg/mL)* | 47.0 [121] | 44.3 [102] | 67.5 [159] | 91.0 [353] | 0.025 |
| Mean RAP (mmHg) | 5.0 (3.1) | 5.6 (3.7) | 5.7 (3.3) | 6.5 (3.7) | 0.050 |
| Mean PAP (mmHg) | 35.4 (10.8) | 32.9 (9.0) | 39.1 (10.5) | 42.1 (9.7) | < 0.001 |
| PAWP (mmHg) | 8.6 (3.4) | 8.8 (4.2) | 8.6 (3.3) | 9.1 (3.9) | 0.757 |
| Cardiac index (L/min/m2) | 2.72 (0.69) | 2.45 (0.59) | 2.56 (0.68) | 2.45 (0.82) | 0.007 |
| PVR (dynes.s. cm–5) | 570 (339) | 580 (324) | 671 (343) | 820 (467) | < 0.001 |
| SvO2 (%) | 65.9 (7.8) | 65.6 (8.3) | 64.9 (8.0) | 60.8 (8.9) | 0.002 |
| Hemodynamics and characteristics at last follow‐up | |||||
| NYHA‐Fc I/II/III/IV (%) | 11/59/27/3 | 34/53/10/3 | 27/59/14/0 | 11/55/32/2 | < 0.001 |
| 6MWD (m) | 391 (109) (n = 53) | 401 (119) | 409 (114) | 377 (123) | 0.304 |
| BNP (pg/mL)* | 26.6 [58.1] | 21.0 [37.0] | 21.0 [34.4] | 27.5 [44.1] | 0.146 |
| Mean RAP (mmHg) | 4.3 (3.1) (n = 44) | 4.2 (2.6) | 4.5 (2.8) | 3.3 (2.3) | 0.057 |
| Mean PAP (mmHg) | 24.7 (8.7) (n = 70) | 20.4 (5.0) | 22.9 (6.7) | 26.1 (8.6) | < 0.001 |
| PAWP (mmHg) | 8.1 (3.2) (n = 45) | 8.3 (3.3) | 8.3 (3.3) | 8.0 (3.1) | 0.891 |
| Cardiac index (L/min/m2) | 2.86 (0.50) (n = 70) | 2.56 (0.58) | 2.78 (0.70) | 2.71 (0.45) | 0.011 |
| PVR (dynes.s. cm–5) | 306 (179) (n = 70) | 263 (119) | 275 (121) | 353 (214) | 0.022 |
| SvO2 (%) | 69.1 (7.0) (n = 68) | 69.4 (5.8) | 70.1 (5.9) | 69.1 (5.1) | 0.376 |
| Change in mean PAP (mmHg) | –11.8 (10.8) (n = 70) | –12.4 (9.9) | –16.2 (10.5) | –15.5 (11.4) | 0.007 |
| % decrease of PVR (%) | 37.2 (35.4) (n = 70) | 45.7 (29.8) | 52.4 (23.1) | 44.3 (35.9) | 0.056 |
Abbreviations: 6MWD, 6‐min walk distance; BMI, body mass index; BNP, Brain natriuretic peptide; DLCO, diffusing capacity for lung carbon monoxide; DOAC, direct oral anticoagulation; ERA, endothelin‐receptor antagonists; FEV1.0, forced expiratory volume in one second; FVC, forced vital capacity; NYHA‐Fc, New York Heart Association functional class; PaO2, partial pressure of arterial oxygen; PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PDE5‐I, phosphodiesterase type‐5 inhibitors; PVR, pulmonary vascular resistance; RAP, right atrial pressure; sGC, soluble guanylate cyclase; SvO2, mixed venous oxygen saturation; VKA, vitamin K antagonist; VTE, venous thromboembolism.
Data are given as mean (standard deviation) or median [interquartile range]
*BNP upper limit of normal value: 18.4 pg/mL.
**one‐way ANOVA: comparison between variables of Med 0 to BPA group, Med 1 to BPA group, and Med ≥ 2 to BPA group.
3.2. Survival and Prognosis
During a median follow‐up period of 35.2 months (first quartile: 15.2 months; third quartile: 51.5 months), 20 of 557 patients (3.6%) died mainly due to right heart failure (n = 16) and clinical worsening of PH (n = 4). The 1‐ and 3‐year survival rates of patients treated with BPA were 99.5% and 96.7%, compared with 95.5% and 89.8% in patients in the No BPA group (p = 0.004, Cox–Mantel log‐rank test), respectively. Figure 2 shows the Kaplan–Meier survival estimates for each treatment group. The prognoses among patients treated with BPA did not differ according to the number of pretreatment drugs.
Figure 2.
Kaplan–Meier estimates of 5–year survival in patients with no pretreatment before BPA (n = 111), patients with medical monotherapy before BPA (n = 242), patients with combination medical therapy before BPA (n = 53), and patients with no treatment or medical therapy only (n = 151); p = 0.857 (Cox–Mantel log‐rank test) comparison between patients who underwent BPA.
3.3. Balloon Pulmonary Angioplasty Outcomes
The hemodynamic and functional classes at the last follow‐up are summarized in Table 1. Patients pretreated before BPA tended to have residual PH and worse functional class at the last follow‐up, reflecting severe pre‐interventional hemodynamics. However, the groups did not differ in the % decrease in PVR. Mean PAP of the Med 1 to BPA group at the last follow‐up was higher than that of the Med 0 to BPA group (p < 0.001); mean PAP of the Med ≥ 2 to BPA group was higher than those of the Med 0 to BPA group (p < 0.001) and Med 1 to BPA group (p = 0.041). Cardiac index of the Med 1 to BPA group at the last follow‐up was higher than that of the Med 0 to BPA group (p = 0.007). PVR of the Med ≥ 2 to BPA group at the last follow‐up was higher than those of the Med 0 to BPA group (p = 0.017) and Med 1 to BPA group (p = 0.038). The absolute change in mean PAP of the Med 1 to BPA group was greater than that of the Med 0 to BPA group (p = 0.005).
4. Balloon Pulmonary Angioplasty Post‐Treatment Analysis
4.1. Patient Population
The patient cohort for the BPA post‐treatment analysis is shown in Figure 3. Among the 1338 patients who underwent follow‐up, 966 patients underwent BPA at or after registration. Of these, 350 patients received no pretreatment drugs before or during BPA (No pretreatment group); 503 patients received pretreatment with medical monotherapy (Monotherapy group); 113 patients received pretreatment with combination medical therapy (Combination therapy group). Figure 4 shows the transition of medical therapy before and during the BPA and at the last follow‐up.
Figure 3.
Patients study cohort of BPA post‐treatment analyses (n = 966).
Figure 4.
Transition of medical therapy between before or during BPA and at last follow‐up.
4.2. De‐Escalation of Medical Therapy
In the Monotherapy and Combination therapy groups, 138 of the 616 patients (22.4%) underwent de‐escalation of medical therapy. Of these, 103 of 503 patients in the Monotherapy group discontinued treatment, 10 of 103 patients in the Combination therapy group discontinued treatment, and 25 patients in the Combination therapy group transitioned to monotherapy. Table 2 summarizes the hemodynamics and characteristics of the medical therapy de‐escalation and non‐de‐escalation (i.e., continuous or escalated medical therapy) groups after BPA. Patients with de‐escalated medical therapy had a better functional status with NYHA‐Fc I and lower mean PAP at the last follow‐up; however, cardiac index was lower than that of the non‐de‐escalation group. Cardiac index of the de‐escalation group did not improve (2.74 ± 0.81 to 2.66 ± 0.61 L/min2, p = 0.913), whereas that of the non‐de‐escalation group improved at the last follow‐up (2.70 ± 0.73 to 2.84 ± 0.70 L/min2, p < 0.001).
Table 2.
Hemodynamics and characteristics between medical therapy de‐escalation group and non‐de‐escalation group after BPA in patients with pretreatment of medical therapy (n = 616).
| Variable | Med de‐escalation group (n = 138) | Med continuous or escalation group (n = 478) | p value |
|---|---|---|---|
| Med 1 to 0 (n = 103)Med ≥ 2 to 1 (n = 25)Med ≥ 2 to 0 (n = 10) | Med 1 (n = 376)Med ≥ 2 (n = 78)Med 1 to ≥ 2 (n = 24) | ||
| Age (years) | 66.4 (11.8) | 67.3 (12.5) | 0.494 |
| Gender, Female | 101 (73%) | 338 (70.7) | 0.571 |
| Combination therapy (≥ 2 drugs before BPA) | 35 (25.4%) | 78 (16.3%) | 0.016 |
| Hemodynamics and characteristics at registration | |||
| NYHA‐Fc I/II/III/IV (%) | 9/43/45/3 | 9/51/37/3 | 0.316 |
| 6MWD (m) | 365 (125) | 367 (118) | 0.849 |
| BNP (pg/mL)* | 36.5 [102.8] | 44.0 [111.8] | 0.541 |
| Mean RAP (mmHg) | 4.9 (2.6) | 5.7 (3.8) | 0.004 |
| Mean PAP (mmHg) | 34.0 (11.8) | 34.4 (12.3) | 0.735 |
| PAWP (mmHg) | 8.3 (3.4) | 9.0 (3.5) | 0.043 |
| Cardiac index (L/min/m2) | 2.74 (0.81) | 2.70 (0.73) | 0.587 |
| PVR (dynes.s. cm–5) | 558 (379) | 549 (382) | 0.810 |
| SvO2 (%) | 67.3 (7.8) | 65.5 (8.5) | 0.039 |
| Hemodynamics and characteristics at last follow‐up | |||
| NYHA‐Fc I/II/III/IV (%) | 35/51/13/1 | 24/62/13/1 | 0.033 |
| NYHA‐Fc I | 49 (35%) | 114 (24%) | 0.006 |
| 6MWD (m) | 421 (129) | 397 (115) | 0.093 |
| BNP (pg/mL)* | 20.0 [30.4] | 26.1 [42.2] | 0.334 |
| Mean RAP (mmHg) | 3.7 (2.4) | 4.6 (2.7) | 0.028 |
| Mean PAP (mmHg) | 20.9 (5.8) | 24.1 (7.3) | < 0.001 |
| PAWP (mmHg) | 7.7 (3.8) | 8.6 (3.1) | 0.083 |
| Cardiac index (L/min/m2) | 2.66 (0.61) | 2.84 (0.70) | 0.010 |
| PVR (dynes.s. cm–5) | 266 (146) | 285 (149) | 0.204 |
| SvO2 (%) | 70.4 (6.0) | 69.6 (5.9) | 0.209 |
| Change in mean PAP (mmHg) | –13.8 (12.0) | –11.9 (10.9) | 0.104 |
| % decrease of PVR (%) | –37.8 (44.5) | –40.4 (32.4) | 0.545 |
Abbreviations: 6MWD, 6‐min walk distance; BNP, Brain natriuretic peptide; BPA, balloon pulmonary angioplasty; NYHA‐Fc, New York Heart Association functional class; PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SvO2, mixed venous oxygen saturation.
Data are given as mean (standard deviation) or median [interquartile range]
*BNP upper limit of normal value: 18.4 pg/mL.
4.3. Escalation of Medical Therapy
In the No pretreatment and Monotherapy groups, 80 of 853 patients (9.4%) required escalated medical therapy. Of these, 51 of 350 patients in the No pretreatment group escalated to medical monotherapy; 5 patients in the No pretreatment group to combination medical therapy; 24 of 503 patients in the Monotherapy group to combination medical therapy. Table 3 summarizes the hemodynamics and characteristics of the medical therapy escalation and non‐escalation (i.e., continuous or de‐escalation of medical therapy) groups after BPA. Patients with escalated medical therapy had worse functional status with NYHA‐Fc III and IV and higher mean PAP at the last follow‐up; however, cardiac index was higher than that in the non‐escalation group. Cardiac index of the escalation group improved (2.67 ± 0.58 to 3.03 ± 1.08 L/min2, p = 0.036) and that of the non‐escalation group also improved at the last follow‐up (2.67 ± 0.71 to 2.70 ± 0.65 L/min2, p = 0.011).
Table 3.
Hemodynamics and characteristics between medical therapy escalation group and non‐escalation group after BPA in patients with no pretreatment or monotherapy at baseline (n = 853).
| Variable | Med escalation group (n = 80) | Med non‐escalation group (continuous or de‐escalation) (n = 773) | P value |
|---|---|---|---|
| Med 0–1 (n = 51) Med 0 to ≥ 2 (n = 5)Med 1 to ≥ 2 (n = 24) | Med 0 (n = 294) Med 1 (n = 376) Med 1 to 0 (n = 103) | ||
| Age (years) | 67.5 (13.0) | 67.1 (13.4) | 0.425 |
| Gender, Female | 61 (76.3%) | 563 (72.8%) | 0.512 |
| No medication before BPA | 56 (70.0%) | 294 (38.0%) | < 0.001 |
| Hemodynamics and characteristics at registration | |||
| NYHA‐Fc I/II/III/IV (%) | 6/56/34/4 | 18/49/31/2 | 0.036 |
| 6MWD (m) | 365 (106) | 389 (122) | 0.131 |
| BNP (pg/mL)* | 48.5 [136.2] | 32.0 [73.0] | 0.185 |
| Mean RAP (mmHg) | 6.3 (4.6) | 5.2 (3.4) | 0.054 |
| Mean PAP (mmHg) | 36.5 (12.2) | 30.6 (11.7) | < 0.001 |
| PAWP (mmHg) | 9.2 (4.2) | 8.7 (3.6) | 0.236 |
| Cardiac index (L/min/m2) | 2.67 (0.58) | 2.67 (0.71) | 0.993 |
| PVR (dynes.s. cm–5) | 568 (300) | 470 (337) | 0.013 |
| SvO2 (%) | 65.7 (8.7) | 67.3 (7.7) | 0.113 |
| Hemodynamics and characteristics at last follow‐up | |||
| NYHA‐Fc I/II/III/IV (%) | 20/62/18/0 | 35/55/9/1 | 0.007 |
| NYHA‐Fc III or IV | 14 (18%) | 75 (10%) | 0.030 |
| 6MWD (m) | 410 (97) | 413 (123) | 0.850 |
| BNP (pg/mL)* | 22.5 [31.4] | 23.3 [38.0] | 0.566 |
| Mean RAP (mmHg) | 4.1 (1.9) | 4.6 (2.7) | 0.185 |
| Mean PAP (mmHg) | 23.9 (6.6) | 21.6 (6.2) | 0.004 |
| PAWP (mmHg) | 8.7 (3.5) | 8.5 (3.3) | 0.748 |
| Cardiac index (L/min/m2) | 3.03 (1.08) | 2.70 (0.65) | < 0.001 |
| PVR (dynes.s. cm–5) | 270 (146) | 259 (125) | 0.498 |
| SvO2 (%) | 69.6 (7.5) | 70.0 (5.5) | 0.671 |
| Change in mean PAP (mmHg) | –13.9 (11.0) | –10.6 (11.0) | 0.019 |
| % decrease of PVR (%) | –48.1 (25.6) | –34.3 (40.0) | < 0.001 |
Abbreviations: 6MWD, 6‐min walk distance; BNP, Brain natriuretic peptide; BPA, balloon pulmonary angioplasty; NYHA‐Fc, New York Heart Association functional class; PAP, pulmonary artery pressure; PAWP, pulmonary artery wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SvO2, mixed venous oxygen saturation.
Data are given as mean (standard deviation) or median [interquartile range]
*BNP upper limit of normal value: 18.4 pg/mL.
The logistic regression analyses of factors associated with the de‐escalation of medical therapy in patients with pretreatment (n = 616) were also conducted to minimize selection bias and confounding factors (Supplemental Table 1), and NYHA‐Fc I (odds ratio [OR], 2.641; 95% confidence interval [CI], 1.501–4.648; p = 0.001), lower mean PAP (OR, 0.915; 95% CI, 0.869–0.963; p = 0.001), and lower cardiac index (OR, 0.573; 95% CI, 0.373–0.880; p = 0.011) at the last follow‐up were independently associated. The logistic regression analyses of factors associated with the escalation of medical therapy in patients with no or monotherapy (n = 853) showed that NYHA‐Fc III or IV (OR: 2.532, 95% CI: 1.068–6.003, p = 0.035), higher mean PAP (OR: 1.092, 95% CI: 1.032–1.155, p = 0.002), and higher cardiac index (OR: 1.787, 95% CI: 1.120–2.852, p = 0.015) at last follow‐up were independently associated (Supplemental Table 2).
4.4. Survival in Post‐Treatment Analysis
Figure 5 shows the Kaplan‐Meier survival estimates in patients with de‐escalation, continuation, and escalation of medical therapy (p = 0.0516, Cox–Mantel log‐rank test). The escalation group had worse survival compared to the continuous group or the de‐escalation group (p = 0.017, p = 0.042, respectively by Cox‐Mantel log‐rank test).
Figure 5.
Kaplan–Meier estimates of 5–year survival in patients with de‐escalation (n = 138), continuation (n = 748), and escalation of medical therapy after BPA (n = 80); p = 0.0516 (Cox–Mantel log‐rank test).
5. Discussion
The present study describing one of the world's largest nationwide cohorts of patients with non‐operable CTEPH showed that approximately 70% of patients received pretreatment with medical therapy before BPA. Patients with severe baseline hemodynamics tended to receive pretreatment therapy; however, the 3‐year survival of patients who underwent BPA was favorable, and survival did not differ between the pretreatment groups. After BPA, almost 20% of patients underwent de‐escalation, and 15% of patients without pretreatment were initiated on medical therapy. Patients who underwent de‐escalation of medical therapy had a better functional class or mean PAP at the last follow‐up; however, cardiac index was impaired compared to that of patients who did not.
Patient cohort from other countries where BPA is well performed as an established treatment strategy showed that 72% of patients received pretreatments (of these, 1% received combination medical therapy) in Poland [12]; 56% (16% received combination medical therapy) in Austria [13]; 62% (35% received combination medical therapy) in France [14]; and, 78% (32% received combination medical therapy) in the United States [15]. The ratio of combination medical therapy varied widely across countries; however, approximately 60–80% of patients received pretreatment with medical therapy before BPA, thereby corroborating our results.
The role of medical therapy in non‐operable CTEPH has been established. Several randomized controlled trials (RCTs) of medical therapies including riociguat, macitentan, and selexipag have demonstrated a positive impact on hemodynamics or 6‐min walking distance [16, 17, 18]. The international prospective CTEPH registry before the BPA era showed that treatment with PAH drugs was not associated with survival in patients with non‐operable CTEPH as per the multivariate Cox hazard analyses [5]. However, this finding must be interpreted with caution because of the potential bias, in that medical treatments are more frequently used in patients with worse functional and hemodynamic profiles.
Pretreatment before BPA has been empirically performed worldwide [12, 14, 19, 20]. Almost all retrospective BPA registries have an aforementioned bias that patients with worse hemodynamics tended to receive medical pretreatment more frequently [5, 7, 21]. RACE trial, the RCT comparing the efficacy of BPA versus riociguat therapy in patients with non‐operable CTEPH from France, reported fewer serious BPA‐related adverse events in patients pretreated with riociguat in the RACE follow‐up study at week 52. PVR and cardiac index before BPA were less severe in the first‐line riociguat group than in the first‐line BPA group [9]. These findings suggest the potential benefits of a sequential approach combining medical treatment and BPA, and the 2022 European Society of Cardiology/European Respiratory Society guidelines for PH propose that medical therapy should be considered prior to BPA in patients with PVR > 4 Wood units to minimize interventional complications as a class IIa recommendation [22]. However, from a hemodynamic point of view, the final PVR of the first‐line riociguat then BPA group and first‐line BPA group were similar in this RCT [9].
Medical treatment was more frequent in patients with poorer functional and hemodynamic profiles. The final hemodynamics of patients who received medical pretreatment tended to be severe, reflecting severe pre‐interventional hemodynamics. The percentage decrease in PVR did not significantly differ according to medical pretreatment. However, this does not indicate that medical pretreatment is ineffective for patients with non‐operable CTEPH. The survival of these patients was favorable, regardless of their baseline hemodynamic status, with an appropriate multimodal approach combining medical therapy and BPA. Similarly, patients who escalated medical therapy following BPA had a worse prognosis in the post‐treatment analysis, which might also reflect severe post‐interventional conditions.
De‐escalation of medical therapy following BPA remains controversial. Pretreatment is recommended in the current guidelines, mainly for safety reasons, with evidence from the RACE trial [9]. A scientific statement on BPA from the American Heart Association recommends weaning of pulmonary vasodilator medications after effective BPA [23]. However, there are no clear criteria or trials that support the de‐escalation of medical therapy after BPA. BPA cohorts from other countries showed that some patients could be weaned from medical therapy at the rate of 56% to 42% (combination therapy: 16% to 9%) in Austria [13] and 85% to 75% (combination: 39% to 36%) in the United States [15]. The rate of de‐escalation was not uniform; however, medical therapy tended to be continued without complete discontinuation in many cohorts [12, 19, 24]. A large monocentric BPA cohort in Japan reported that the proportion of patients requiring combination medical therapy decreased from 40% to 10% 1 year after BPA, and improved hemodynamics and functional status were almost maintained regardless of discontinuation [25]. In the present study, approximately 20% of the patients who received pretreatment underwent de‐escalation of medical therapy. Patients who underwent de‐escalation in medical therapy had a better functional class or mean PAP at the last follow‐up, and favorable survival. However, cardiac index of the de‐escalation group was more impaired compared with that of the non‐de‐escalation group (p = 0.010). Moreover, cardiac index of the de‐escalation group did not improve from registration to the last follow‐up (p = 0.913), whereas that of the non‐de‐escalation group improved (p < 0.001) in the present study. Continuation of medical therapy after BPA may significantly affect cardiac index. Another large Japanese monocentric BPA cohort also reported that increasing cardiac output with BPA alone might be challenging in older patients, and the continuation of medical therapy should be considered even after successful BPA in these patients [26]. De‐escalation or continuation of medical therapy should be carefully considered even after mean PAP normalizes after BPA.
Another finding of the present study is that more patients with non‐operable CTEPH underwent BPA therapy in Japan compared to the international CTEPH registry, in which only 46% of non‐operable CTEPH underwent BPA [7]. In the CTEPH AC registry, 86% of non‐operable CTEPH underwent BPA, and this accessibility and frequency of BPA might contribute to the excellent survival in non‐operable CTEPH in Japan.
5.1. Limitation
The main limitation of this study is its observational nature. Therefore, the decision of initiation of medical therapy and continuation or discontinuation was left to the discretion of each investigator, as there were no criteria for medical therapy. Therefore, accurately evaluating the role of pre‐ or post‐treatment might be difficult. Furthermore, the CTEPH AC Registry did not collect data on BPA‐related complications or periprocedural deaths. Therefore, the clinical impact of pretreatment on the safety of BPA could not be assessed within this registry. Another limitation was that the intervals from baseline assessment to the first BPA and from BPA completion to follow‐up RHC were not uniform. In addition, some patients may not have completed treatment at the time of the last follow‐up, which could introduce bias.
6. Conclusion
Approximately 70% of patients in Japan received pretreatment with medical therapy before BPA. Patients with severe baseline hemodynamics tended to receive pretreatment therapy more frequently; however, the 3‐year survival of patients who underwent BPA was favorable, and the survival did not significantly differ across the no, mono, and combination pretreatment groups. After BPA, almost 20% of patients underwent de‐escalation of medical therapy. Patients who underwent de‐escalation had better functional class or mean PAP at the last follow‐up; however, their cardiac index was impaired compared with that of patients who did not. De‐escalation or continuation of medical therapy should be carefully considered even after mean PAP normalizes after BPA.
Author Contributions
Y.T, M.S‐I, K.M, K.H, and K.A were responsible for design, analysis and interpretation of data. Y.T, M.S‐I, S.H, T.I, J.Y, H.O, M.H, I.T, N.Y, N.I, H.S, N.T, K.K, A.S, Y.O, K.H, Y.D, T.H and T.K participated to data collection. Y.T and M.S‐I prepared the manuscript. Y.T, Y.F and K.A were responsible for manuscript review and revision. All authors contributed to manuscript review and revision. All authors approved the final version of the manuscript.
Ethics Statement
The CTEPH AC registry complied with the Declaration of Helsinki and was approved by the institutional review board of each institution. The study was registered in the UMIN Clinical Trials Registry, an open‐access database (UMIN 000033784).
Consent
Written informed consent forms were obtained from patients at registry enrollment.
Conflicts of Interest
Dr Taniguchi has received grants from Nippon Shinyaku and Janssen Pharmaceutical; and personal fees from Nippon Shinyaku, Janssen Pharmaceutical, and Bayer Yakuhin, outside the submitted work. Dr Hosokawa has received grants from Konica Minolta; and personal fees from Bayer Yakuhin, Nippon Shinyaku, Janssen Pharmaceutical, Pfizer, and Konica Minolta, outside the submitted work. Dr Inami has received personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside the submitted work. Dr Yamashita has received a grant from Abbott Vascular Japan and personal fees from Kaneka Medix, Boston Scientific Japan, Nihon Kohden, Philips Japan, Janssen Pharmaceutical, and Bayer Yakuhin, outside the submitted work. Dr Ogino has received consulting fees from Terumo, Japan Lifeline, and Century Medical; and personal fees from Bayer Yakuhin, Daiichi‐Sankyo, Pfizer, and Nippon Shinyaku, outside the submitted work. Dr Hatano has received personal fees from Bayer Yakuhin and Janssen Pharmaceutical, outside the submitted work. Dr Tsujino has received personal fees from Nippon Shinyaku and Janssen Pharmaceutical; and affiliation with the division supported by endowments from Nippon Shinyaku, Nippon Boehringer Ingelheim, Mochida Pharmaceutical, Kaneka Medix, Takeyama, and Medical System Network, outside the submitted work. Dr Yaoita has received personal fees from Bayer Yakuhin and Konica Minolta, outside the submitted work.
Dr Ikeda has received personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi ‐Sankyo, and Bristol Myers Squibb, outside the submitted work. Dr Shimokawahara has received a grant from Bayer Yakuhin and personal fees from Bayer Yakuhin and Nippon Shinyaku, outside the submitted work. Dr Tanabe has received personal fees from Janssen Pharmaceutical, Bayer Yakuhin, and Nippon Shinyaku, outside the submitted work. Dr Kubota has received personal fees from Janssen Pharmaceutical and Nippon Shinyaku, outside the submitted work. Dr Ogihara has received grants from Bayer Yakuhin and personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi‐Sankyo, and Bristol Myers Squibb, outside the submitted work. Dr Kawakami has received personal fees from Kaneka Medix and Abbott Medical Japan, and consulting fees from ACIST Japan, outside the submitted work. Dr Tamura has received grants from Bayer Yakuhin, Nippon Shinyaku, and Mochida Pharmaceutical; and personal fees from Bayer Yakuhin, Nippon Shinyaku, Daiichi‐Sankyo, and Janssen Pharmaceutical, outside the submitted work. Dr Abe has received a grant from Konica Minolta and Daiichi‐Sankyo, outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Guarantor
Yu Taniguchi is the guarantor of this study.
Supporting information
Supporting File
Acknowledgments
We appreciate Prof. Hiromasa Otake for his supervision. We also thank the research administrators and healthcare professionals who helped set up and deliver the study to all 37 institutions, as well as all the supporting staff at the 37 institutions across Japan. Japan Agency for Medical Research and Development (grant numbers JP20ek0109371, JP19lk0201102, JP22lk0201125, and JP19lk1601003). The funding body had no influence on the study design or results.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting File
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.