1. INTRODUCTION

Chronic thromboembolic pulmonary hypertension (CTEPH), classified group 4 pulmonary hypertension (PH), is characterized by obstruction of the pulmonary vasculature by organized thromboembolic material and vascular remodeling due to previous pulmonary embolism (PE).1 Poor prognosis for CTEPH such as right heart failure and death can occur if patients with CTEPH do not receive appropriate management.2 According to Kim et al1, a 3-year survival rate for patients with CTEPH receiving medical treatment was 70%. It is critical to target those patients and provide appropriate management.

According to 2022 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines for the diagnosis of PH,3 CTEPH should be considered in patients with associated symptoms of PH and PE history. Various diagnostic techniques for CTEPH, including echocardiography, right heart catheterization (RHC), pulmonary angiography, tomographic pulmonary angiography (CTPA), and ventilation/perfusion (V/Q) scans, should be provided to target these patients. The diagnostic criteria for CTEPH were as follows: (1) any mismatched perfusion defects in the V/Q scan and intermediate/high probability of PH detected by echocardiography; and (2) specific diagnostic signs for CTEPH detected by CTPA and RHC.

Several management strategies have been provided for patients with CTEPH, including pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and PH-targeted medical therapy.4 In 2016, Delcroix et al reported that a 3-year survival rate of patients with operatable CTEPH was 89%, and a high long-term survival rate of patients with CTEPH who were treated with BPA has also been identified in previous studies.5–7 Compared to medical treatment only for CTEPH patients, invasive intervention seems to provide better outcomes in patients with CTEPH. However, long-term outcomes of patients with CTEPH who have undergone interventions in Taiwan are inconclusive. Thus, our study aimed to estimate the long-term impact of this intervention in CTEPH patients.

2. METHODS 2.1. Study design and patient selection

This was a multicenter, prospective case-control study. Patients diagnosed with CTEPH at six medical centers in Taiwan (National Taiwan University Hospital, Cheng Hsin General Hospital, Mackay Memorial Hospital, China Medical University Hospital, National Cheng Kung University Hospital, and Kaohsiung Veterans General Hospital) between January 2018 and March 2020 were enrolled in this study. The diagnostic protocol was based on the CTEPH guidelines8 and these enrolled patients received standard medical treatment for CTEPH once the diagnosis was confirmed. Standard medical treatment included anticoagulant drugs such as vitamin K antagonist (VKA) and novel oral anticoagulant (NOAC), soluble guanylyl cyclase (sGC) stimulators, PDE-5 inhibitors, endothelin receptor antagonists, and prostanoid therapy. After assessing patients’ condition, their doctors would decide what kinds of treatment were available to them. Basically, patients were treated with invasive interventions, such as PEA and BPA, or without interventions. The intervention and nonintervention groups were defined as intervention and conservative groups, respectively. Parameters associated with disease severity were demonstrated, including World Health Organization (WHO) functional class (Fc), b-type natriuretic peptide (BNP), left ventricular ejection fraction, mean pulmonary arterial pressure, N-terminal pro-BNP (NT-proBNP), pulmonary capillary wedge pressure (PCWP), pulmonary vascular resistance, and 6-minute walk test.

The Research Ethics Committee of all hospitals reviewed and approved this study (ClinicalTrials.gov Identifier: NCT03667391), and informed consent was obtained from all patients.

The outcomes of our study were defined as all-cause death and CTEPH death in the enrolled patients with CTEPH with or without intervention. Each enroller was followed up as an outpatient and by telephone visits after starting treatment for CTEPH and the reasons for death were identified from medical records.

2.2. Statistical analysis

Clinical data on comorbidities, diagnostic procedures for CTEPH, types of invasive procedures for CTEPH, pulmonary arterial hypertension-targeted medicine use, and clinical follow-up visits were retrieved from the medical records. The statistical analysis system version 9.4 software (SAS Institute Inc., Cary, NC) was used for all analyses. Descriptive statistics were calculated for all variables, with categorical data reported as percentile values and continuous variables reported as means and SDs. Between-group differences were evaluated by paired t test for continuous variables and chi-squared test for categorical variables, with statistical significance being set at p < 0.05. Kaplan-Meier cumulative survival curves were constructed to compare the survival of patients with CTEPH with and without PEA or BPA treatment. Log-rank test with a p < 0.05 were considered statistically significant. Cox proportional hazards regression analysis was used to calculate the hazard ratio (HR), and associated 95% CIs, for significant variables. A p value for interaction <0.05, indicating significant differences between subgroups.

3. RESULTS

In total, 129 patients with CTEPH were enrolled in our study. Basic patient characteristics, diagnoses, hemodynamics, and treatments are shown in Table 1. A total of 73 and 56 patients were enrolled in the intervention and conservative groups, respectively. The patients in the intervention group were younger than those in the conservative group (57.7 vs 67.1 years, p < 0.001). Moreover, there was a higher proportion of severe function classes (WHO Fc: III + IV) in the intervention group than in the conservative group (83.6% vs 58.9%, p = 0.002). In addition, the PCWP in the intervention group was lower than that in the conservative group (11.67 vs 15.06 mm Hg, p = 0.004). For other variants, there were no significant differences between the two groups.

Table 1 - Basic characteristics, diagnosis, hemodynamics, and treatment for CTEPH patients Intervention group Conservative group p n = 73 n = 56 Basic characteristics  Age, y 57.7 ± 16.2 67.1 ± 14.8 <0.001  Male 22 (30.1%) 13 (23.3%) 0.038  Body height, cm 159.9 ± 10.0 157.2 ± 10.3 0.125  Body weight, kg 63.8 ± 14.0 63.6 ± 14.9 0.950  Body mass index 24.88 ± 4.5 25.81 ± 5.8 0.319  Initial WHO functional class <0.001   I+II 12 (16.4%) 23 (41.1%)   III+IV 61 (83.6%) 33 (58.9%) 0.002 Diagnosis  Echocardiography 69 (94.5%) 56 (100%) 0.132  CTA 72 (98.6%) 55 (98.2%) 1.000  Ventilation/perfusion scan 59 (80.8%) 48 (85.7%) 0.231  Right heart catheterization 72 (98.6%) 55 (98.2%) 1.000  6MWT, m 312.2 ± 129.3 329.4 ± 115.4 0.873  NT-proBNP, pg/mL 1942.7 ± 3215.1 1453.2 ± 2618.7 0.519  BNP, pg/mL 1326.1 ± 3290.7 839.5 ± 2300.7 0.622  D-dimer, ng/mL 1434.4 ± 3127.3 459.1 ± 1218.0 0.099 Hemodynamics  Mean PAP, mm Hg 43.89 ± 12.05 39.76 ± 11.80 0.057  PCWP, mm Hg 11.67 ± 5.32 15.06 ± 6.95 0.004  PVR, dyn.s.cm-5 9.16 ± 4.77 31 ± 120.81 0.198  Cardiac output, L/min 4.25 ± 1.58 3.91 ± 1.37 0.214  Cardiac index, L/min/m2 2.54 ± 0.86 2.38 ± 0.77 0.298 Treatment  Vitamin K antagonists 44 (60.2%) 24 (42.8%) 0.041 Novel oral anticoagulant  Rivaroxaban 24 (32.8%) 33 (58.9%) 0.044  Dabigatran 1 (1.3%) 0 (0%)  Edoxaban 1 (1.3%) 1 (1.7%)  Apixaban 15 (20.5%) 5 (8.9%)  Others 0 (0%) 1 (1.7%)  No used 31 (42.4%) 16 (28.5%)  PH medications   sGC stimulator or PDE-5 inhibitor 66 (90.4%) 44 (78.5%) 0.060   Endothelin receptor antagonist 4 (5.4%) 2 (3.5%) 0.069   Prostacyclins 2 (2.7%) 1 (1.7%) 1.000

Continuous data are shown as mean ± standard deviation and categorical data are shown as number (%).

6MWT = 6-minute walk test; BNP = b-type natriuretic peptide; CTEPH = chronic thromboembolic pulmonary hypertension; CTA = Computed tomography angiography; CI = cardiac index; CO = cardiac output; LVEF = left ventricular ejection fraction; mean PAP = mean pulmonary arterial pressure; NT-proBNP = N-terminal pro-b-type natriuretic peptide; PDE-5 inhibitor = phosphodiesterase type 5 inhibitor; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; sGC stimulator = soluble guanylate cyclase stimulator.

The clinical signs, comorbidities, and risk factors of patients are shown in Table 2. The most common clinical sign was dyspnea, followed by exercise intolerance, and lower leg edema. The most common comorbidity was hypertension, followed by acute PE, and dyslipidemia. The proportion of dyslipidemia in the intervention group was higher than that in the conservative group (19.18% vs 37.5%, p = 0.02). The remaining variants in the two groups were not statistically different.

Table 2 - Clinical sigs, comorbidities, and risk factors for CTEPH patient Clinical signs Intervention group Conservative group p n = 73 n = 56  Chest pain 10 (13.7%) 9 (16.07%) 0.706  Cyanosis 2 (2.74%) 1 (1.79%) 1.000  Dizziness 7 (9.59%) 12 (21.43%) 0.060  Dyspnea 64 (87.67%) 51 (91.07%) 0.538  Exercise intolerance 36 (49.32%) 26 (46.43%) 0.745  Fatigue 16 (21.92%) 8 (14.29%) 0.269  Lower leg edema 18 (24.66%) 24 (42.86%) 0.028  Syncope 5 (6.85%) 9 (16.07%) 0.095  Others 11 (15.07%) 8 (14.29%) 0.901 Comorbidities  Acute pulmonary embolism 19 (26.03%) 18 (32.14%) 0.446  Acute coronary syndrome 0 (0.0%) 0 (0%) -  COPD 2 (2.74%) 6 (10.71%) 0.076  Diabetes 11 (15.07%) 11 (19.64%) 0.493  Dyslipidemia 14 (19.18%) 21 (37.5%) 0.020  Hypertension 21 (28.77%) 25 (44.64%) 0.062  Ischemic heart disease 2 (2.74%) 3 (5.36%) 0.652  Left-sided heart failure 1 (1.37%) 3 (5.36%) 0.316  Other disease of endocardium 5 (6.85%) 5 (8.93%) 0.273  Other lung diseases 5 (6.85%) 7 (12.5%) 0.273  Other chronic pulmonary heart disease 4 (5.48%) 0 (0%) 0.132  Sleep apnea 2 (2.74%) 1 (1.79%) 1.0  Stroke 0 (0%) 1 (1.79%) 0.434  Transient ischemia attack 0 (0%) 0 (0%) -  Others 10 (13.7%) 14 (25%) 0.121 Risk factors  Pulmonary embolism 62 (84.93%) 45 (80.3%) 0.791  Antiphospholipid syndrome/Lupus anticoagulant 6 (8.22%) 3 (5.3%) 0.527  Coronary disease or myocardial infarction 6 (8.22%) 10 (17.8%) 0.125  Family history of DVT or PE 1 (1.37%) 0 (0%) 0.668  Fracture 3 (4.11%) 3 (5.36%) 1.0  Hemolytic anemia 2 (2.74%) 4 (7.14%) 0.402  Infection of ventriculoarterial shunt or pacemaker 0 (0%) 0 (0%) -  Inflammatory bowel disease 0 (0%) 3 (5.36%) 0.079  Malignancy 5 (6.85%) 6 (10.71%) 0.530  Type 2 diabetes mellitus 11 (15.07%) 11 (19.64%) 0.493  Obesity (BMI ≥ 30 kg/m2) 11 (15.07%) 7 (12.50%) 0.676  Previous major surgery 15 (20.55%) 8 (14.29%) 0.357  Smoking 14 (19.18%) 6 (10.71%) 0.188  Splenectomy 5 (6.85%) 0 (0%) 0.068  Thyroid disorder and hormone replacement therapy 8 (10.96%) 6 (10.71%) 0.964  Major trauma 0 (0%) 1 (1.79%) 0.434  Varicose veins 5 (6.85%) 1 (1.79%) 0.232  DVT 19 (26.03%) 11 (19.64%) 0.394  Systemic-pulmonary shunt 0 (0%) 4 (7.14%) 0.033

Categorical data are shown as number (%).

- is indicated as cannot be compared due to the value in two groups were 0%.

BMI = body mass index; COPD = chronic obstructive pulmonary disease; DVT = deep vein thrombosis; PE = pulmonary embolism.

Kaplan-Meier cumulative curves were used to evaluate the survival rates of patients with CTEPH with or without PEA or BPA. Regarding all-cause death outcome, the survival rate was higher in the intervention group than in the conservative group (log-rank p = 0.0164, Fig. 1). The 26-month survival rate of patients with CTEPH in the intervention group was 95.89%. In contrast, the 26-month survival rate in the conservative group was 80.36%. Regarding the CTEPH death outcome, the 26-month survival rate in the intervention group was 97.26%, and that in the conservative group was 85.71% (log-rank p = 0.0355, Fig. 2).

Fig. 1:

Kaplan-Meier survival curve of all-cause death of CTEPH patients with PEA or BPA and without intervention. Overall, the 26-mo survival rate was higher on patients with PEA or BPA (95.9% vs 80.4%, p = 0.0164) compared to patients without intervention. BPA = balloon pulmonary angioplasty; CTEPH = chronic thromboembolic pulmonary hypertension; PEA = pulmonary endarterectomy.

Fig. 2:

Kaplan-Meier survival curve of CTEPH death on chronic CTEPH patients with PEA or BPA and without intervention. The 26-mo survival rate of CTEPH death was higher on patients with PEA or BPA (97.3% vs 85.7%, p = 0.0355). BPA = balloon pulmonary angioplasty; CTEPH = chronic thromboembolic pulmonary hypertension; PEA = pulmonary endarterectomy.

Cox proportional-hazard regression analysis, the multivariate analysis, was performed, and the forest plot of HR of subgroup analysis for all-cause death outcome is illustrated in Fig. 3. The PEA or BPA management was indicated as an independent variant to the all-cause death outcome on patients with CTEPH (HR = 0.07; 95% CI, 0.01-0.59; p = 0.02). According to the outcome of CTEPH death, PEA or BPA was also shown as an independent variant (HR = 0.11; 95% CI, 0.01-0.59; p = 0.0461, Fig. 4). With regard to other subgroups including gender, age ≥65 years, body mass index (BMI) ≥30, severe WHO fc (III + IV), and BNP >300 ng/L, other comorbidities such as PE, chronic obstructive pulmonary disease, and diabetes, and medical treatment including VKA, NOAC, and sGC simulator, all-cause death and CTEPH death outcomes were not statistically affected.

Fig. 3:

Forest plot of HR and 95% CI of subgroup analysis in all-cause death outcome. Pulmonary endarterectomy or balloon pulmonary angioplasty was the independent variant to all-cause death outcome on CTEPH patients (HRs = 0.07 and p = 0.0142). The rest of factors including BMI ≥30, age ≥65, BNP >300, comorbidities, and medical treatments which are associated with possible CTEPH prognosis and mortality, had no statistical difference. BMI = body mass index; BNP = b-type natriuretic peptide; CTEPH = chronic thromboembolic hypertension patients; HR = hazard ratios; NOAC = novel oral anticoagulant; VKA = vitamin K antagonist; WHO = World Health Organization.

Fig. 4:

Forest plot of HR and 95% CI of subgroup analysis in CTEPH death outcome. Pulmonary endarterectomy or balloon pulmonary angioplasty was the independent variant to CTEPH death outcome on CTEPH patients (HR = 0.11 and p = 0.0461). The rest of factors including BMI ≥30, age ≥65, BNP >300, comorbidities, and medical treatments which are associated with possible CTEPH prognosis and mortality, had no statistical difference. BPA = balloon pulmonary angioplasty; BMI = body mass index; BNP = b-type natriuretic peptide; CTEPH = chronic thromboembolic hypertension patients; HR = hazard ratios; NOAC = novel oral anticoagulant; PEA = pulmonary endarterectomy; sGC = soluble guanylyl cyclase; VKA = vitamin K antagonist; WHO = World Health Organization.

4. DISCUSSION

This multicenter study was the first to compare the long-term outcomes of patients with CTEPH with or without intervention in the Han-Chinese population. A higher survival rate was observed in patients with CTEPH who underwent intervention. Because several diagnostic tools for CTEPH have been recently applied to identify patients, the epidemiology of CTEPH and long-term outcomes of intervention can be properly established.

4.1. Epidemiology, hemodynamics, and mortality of CTEPH

The prevalence of CTEPH according to sex remains inconsistent worldwide. Pepke-Zaba et al9 reported the prevalence of CTEPH was equal in men and women. Liu et al10 reported that the incidence of CTEPH was female predominant (70.6%) in Taiwan. In contrast, the female on male ratio was 0.7 in the American group reported by Nakamura et al.11 The prevalence of CTEPH in our study is female predominant, which is consistent with Liu’s study and it may be the population from the same country. According to previous studies conducted in different countries,4,12,13 the long-term survival rate of patients with CTEPH who do not undergo invasive interventions is relatively poor. A 3-year survival rate for nonoperative patients with CTEPH was 74.3% according to Taniguchi et al.12 According to Delcroix et al,4 the 3-year survival rate for nonoperative patients was 70%. The 1- and 3-year survival rates were 82% and 70%, respectively, for patients with CTEPH according to Condliffe et al.13 In the present study, the 26-month survival rates of patients with CTEPH in the conservative group were 80.36% and 85.71%, respectively (Figs. 1 and 2). As a result, medical treatment only for patients does not seem to provide an ideal long-term outcome and the 20% to 30% of mortality rates within 3 years.

4.2. The impact of PEA and BPA on long-term outcomes in patients with CTEPH

According to Dardi et al,14 CTEPH can be cured by PEA; thus, PEA is recommended as the first-line treatment for patients with CTEPH. Good long-term outcomes and high survival rates in patients with CTEPH receiving PEA have also been reported in previous studies.15–17 A mortality rate of 3% to 7% at 3 to 12 months after PEA was reported in a study by Mayer et al.15 According to Cannon et al,16 the survival rate and quality of life were also improved in patients with CTEPH patients receiving PEA. A 3-year survival rate of 88% to 91% in patients with CTEPH receiving PEA was reported by Saouti et al.17 However, the risks and possible complications of PEA should be evaluated cautiously. The mortality rate for patients with PEA is between 4% and 24%.18 As a result, operatable patients with CTEPH could be considered for PEA treatment early after cautiously assessing their clinical condition. BPA is another option for patients with in-operable CTEPH. Improvements in hemodynamics, symptoms, and exercise capacity in patients with CTEPH after BPA have been reported in several studies in Japan.5,6,19 Inami et al6 reported that the 3- and 5-year survival rates of patients with CTEPH who underwent BPA were 98.0% and 95.5%, respectively. Safety and improvement in quality of life and pulmonary hemodynamics were also reported by Hoole et al20 in the UK. Furthermore, 0% to 3.4% mortality rate of patients with CTEPH undergoing BPA has been reported in previous studies.21,22 According to the low mortality rate of BPA and good outcome in patients with CTEPH, BPA should be considered as an alternative treatment for in-operable patients. In the present study, higher 26-month survival rates were identified in the intervention group for all-cause death and CTEPH death outcomes (95.89% vs 97.26%) (Figs. 1 and 2). A statistically significant difference in the survival rate of all-cause death and CTEPH death was detected between the two groups (p = 0.0164 vs p = 0.0355). The survival rate on patients with CTEPH in the present study was similar to that reported in previous studies worldwide. Furthermore, the results of the Cox proportional hazard regression analysis showed that intervention was an independent variant of the mortality in patients with CTEPH. Patients with CTEPH in the intervention group had better all-cause death outcome and CTEPH death outcome, respectively (HR = 0.07 vs HR = 0.11) (Figs. 3 and 4). Moreover, BMI, age, and BNP are considered as significant risks for death of CTEPH patients in this analysis. According to 2015 ESC/ERS guidelines for the diagnosis and treatment of PH,23 the 6MWD, which is affected by sex, old age, high BMI, and comorbidities reported by Mahmoud et al,24 and BNP are variables to be assessed the prognosis of PH. The level of BNP is used to assess patient’s stability. When BNP is higher than 300 mg/L, it indicates that the patient with PAH is unstable and deteriorating.8,23 Thus, high BMI (≥30), older age (≥65), and elevated BNP (>300 mg/L) are the risk factors associated with prognosis of PH and death. However, the above factors have no difference statistically in the outcome of all-cause death and CTEPH death in this analysis as Figs. 3 and 4 show. Based on these results, PEA and BPA should be considered early in patients with CTEPH who are candidates for intervention.

4.3. Study strengths and limitations

To the best of our knowledge, this is the first multicenter study, involving centers across our entire country. The enrolled patients underwent multiple diagnostic tests and examinations to confirm their diagnoses. This approach allows for a broader and more comprehensive representation of the population. Furthermore, the hemodynamics of patients with CTEPH were recorded completely, and the relationship between the outcome of the intervention and the volume of hemodynamics was estimated. Moreover, our findings are compatible with various international studies. The alignment with global research not only confirms our results but also positions our study as part of a larger body of evidence supporting the conclusions drawn. Finally, our study is able to be a foundation in this field in Taiwan for further research.

The present study has some limitations. First, randomization could not be provided in this prospective case-control study because the patients were assigned to receive a specific treatment. The in-operable patients could not be randomly allocated to the intervention group. A randomized trial should be performed in the future to confirm our findings. Second, statistically significant differences in patient’s characteristics were between the two groups, including the average age and number of patients with severe WHO functional classification. Cox proportional hazards regression was used to correct for these variants. Therefore, the results of this study can be trusted, although a few factors differed between the two groups.

In conclusion, evidence of the impact of PEA and BPA on long-term outcomes in patients with CTEPH in the Han-Chinese population was demonstrated in this multicenter study. Patients with CTEPH receiving PEA or BPA had lower mortality rates than those not receiving PEA and BPA. PEA and BPA are significant variants that provide good long-term outcomes in patients with CTEPH.

ACKNOWLEDGMENTS

This study was supported by grants from the Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, that is, grant numbers KSVGH111-007, KSVGH110-077, VGHKS109-132, VAC110-001-4 and the Ministry of Science and Technology (grant numbers: MOST107-2314-B-075B-008-MY2 and MOST108-2314-B-075B-007-MY2).

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