Insufficiency of quality of life as the treatment endpoint for balloon pulmonary angioplasty in inoperable chronic thromboembolic pulmonary hypertension

Patients

The research related to human use has been complied with all the relevant national regulations, institutional policies, and in accordance with the tenets of the Helsinki Declaration, and has been approved by the Beijing Chaoyang Hospital Ethics Committee (2018-KE-144). CTEPH was diagnosed according to the International Guidelines of Pulmonary Hypertension (2015 ERS/ ESC Guidelines for Pulmonary Hypertension),^[12] in which CTEPH is defined by (1) mean pulmonary arterial pressure (mPAP) ≥25 mmHg and pulmonary arterial wedge pressure (PAWP) ≤15 mmHg confirmed by right heart catheterization (RHC), (2) chronic thrombosis confirmed by mismatched perfusion defects on ventilation/perfusion scanning or computed tomography angiography, and (3) at least 3 months of regular anticoagulation therapy. CTEPH patients were recruited if they (1) were confirmed inoperable by a multidisciplinary team, (2) had received at least four BPA sessions in our center, and (3) were aged ≥18 years. Patients were excluded if they were concomitant with type III or V pulmonary hypertension or had mental illness or could not complete a valid QoL questionnaire. The feasibility of pulmonary endarterectomy was determined by a multidisciplinary team, including physicians, radiologists, and surgeons.^[13]

Informed consent was obtained from all individuals included in this study.

Clinical data collection

The following demographic and clinical data were collected before the first and after each BPA session: age, gender, duration of CTEPH (from onset of symptoms to treatment), number of BPA sessions, symptoms, World Health Organization functional classification (WHO FC), 6-min walk distance (6MWD), laboratory examination, and echocardiography parameters. RHC parameters were also collected before the first BPA session. For QoL assessment, patients completed the RAND 36-item short-form (SF-36v2) questionnaire from the Medical Outcomes Study before and after every two BPA sessions.

RHC data were also collected 4–6 months after the last BPA session and considered as follow-up records. At the same time, the physical component summary (PCS) scores and the mental component summary (MCS) scores from the SF-36v2 for these patients were used as follow-up data.

BPA procedure

BPA was performed by two skilled interventional radiologists. A conventional femoral venipuncture was made. A 6F JR- or JL-guided catheter (Launcher; Cordis, Miami Lakes, FL, USA) was introduced to the target vessel by a guidewire. A 2-mm balloon was used for the first vascular expansion. Then, the balloon was gradually inflated to a size no larger than the target vessel. If pulmonary artery injury occurred during the operation, the balloon was immediately deflated. If this was not practical, a gelatin sponge was used. Two oral anticoagulants, warfarin or rivaroxaban, were routinely used after BPA. For warfarin use, the international normalized ratio was maintained between 2.0 and 3.0.

The odd-numbered intervals between BPA sessions were no less than 2 weeks, and the even-numbered intervals were no less than 1 month. The number of BPA sessions, total number of dilated vessels (segmental level), and number of dilated vessels per session were recorded.

Right heart catheterization

RHC was performed in all patients using a Philips monitoring system (Shenzhen Goldway Industrial Inc., Shenzhen, China) on the day of admission and after every two sessions of BPA to record hemodynamic factors. Briefly, a Swan-Ganz catheter was inserted via the jugular vein to assess the pressure in the right ventricle and pulmonary artery. The mPAP was recorded, and oximetry samples were obtained. The PAWP was calculated to exclude post-capillary pulmonary hypertension. The cardiac output (CO) was calculated using thermodilution, and the mean values from triplicate measurements are provided. The pulmonary vascular resistance (PVR) was calculated using the formula PVR = (mPAP – PAWP)/ CO. Pulmonary angiography was performed for bilateral pulmonary arteries at baseline.

Assessment of QoL

The SF-36v2 (Chinese version) has been previously used by us to evaluate the QoL of CTEPH patients.^[14] In the present study, SF-36v2 data were collected at baseline and after every two BPA sessions. The patients were asked to complete the questionnaire using an online survey platform on a smartphone application called Questionnaire Star. For patients who did not have a smartphone, the questionnaire was administered by a doctor. The SF-36v2 score describes the overall health status of the patients in eight different domains—physical functioning (PF), bodily pain (BP), general health (GH), role-emotional (RE), role-physical (RP), social functioning (SF), vitality (VT), and mental health (MH).

The results of the questionnaire were transformed to a score of 0–100, and the scores obtained before and after BPA treatment were compared. The PCS and MCS scores were recorded at each assessment.

Statistical analysis

All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 25 (SPSS Inc., Chicago, IL, USA). Data for non-normally distributed continuous variables are presented as the median and interquartile range. Data for continuous variables at baseline and after BPA were compared using the Wilcoxon’s signed-rank test. The categorical data, including gender, WHO FC, and general health condition, are presented as percentages and were compared using the Chi-squared test.

Receiver operating characteristic (ROC) curve analysis was performed to determine the PCS level that provided the best combination of sensitivity and specificity for predicting the WHO FC before and after BPA treatment. Patients were then divided into two groups according to the cutoff PCS score at baseline and after treatments, respectively. The Spearman correlation coefficient for rank data was used to estimate the association between hemodynamic status and PCS/MCS before and after BPA. Friedman’s test (Wilcoxon’s signed-rank test between the two groups with post hoc analysis) was used to compare the hemodynamic parameters from RHC, 6MWD, and clinical data between different stages. The level of statistical significance was set at P < 0.05.

Demographic and clinical characteristics of patients at baseline

A total of 40 patients (11 males and 29 females) were enrolled in this study. The mean patient age was 58.5 ± 10.7 years, and the median duration of CTEPH from symptom onset to therapy was 5 (3, 9) years. All 40 patients (100%) complained of dyspnea, while chest congestion was reported by 37 patients (93%), edema of a lower extremity by 27 patients (68%), and transient syncope by eight patients (20%). Among all participants, 13 were classified as WHO FC II, 20 patients as WHO FC III, and seven patients as WHO FC IV. The baseline hemodynamic measurements included a mPAP of 50.7 ± 11.2 mmHg, PVR of 913.9 ± 338.2 dyn·s⁻¹·m⁻⁵, and cardiac index (CI) of 2.27 ± 0.60 L·min⁻¹·m⁻². Before BPA treatment, 32 patients were receiving targeted drug therapy (Table 1).

Changes in hemodynamics, clinical parameters, and QoL scores before and after BPA

A total of 176 BPA sessions were performed from January 12, 2017 to July 12, 2020. The median number of BPA sessions per patient was 4 (4, 4.75), and the median total number of dilated vessels per patient was 22 (18.5, 26) (Table 1). Guidewire-related pulmonary artery injury occurred in five cases, and all of the patients presented with cough. Only one patient presented with hemoptysis, which stopped after vessel inflation. No case of reperfusion pulmonary edema was observed.

Comparisons of clinical factors from before to after multiple BPA sessions (four to six procedures) are presented in Table 2 and Figure 1. After several procedures of BPA, the proportion of patients classified as WHO FC III/IV decreased from 67.5% to 30% (P < 0.001), and the median N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) also decreased from 1139.5 (287.8, 3505.3) to 126.5 (72.8, 1077) pg/mL. Meanwhile, the oxygen arterial pressure of indoor air (PaO₂) increased from 58.3 ± 8.3 to 65.5 ± 9.8 mmHg (P < 0.001), the mixed venous oxygen saturation (SvO₂) increased from 57.1% ± 9.3% to 60.5% ± 8.0% (P = 0.042), and the 6MWD increased from 354 (269, 433) to 455 (322, 499) m (P < 0.001). With respect to hemodynamic parameters, the median mPAP and mean PVR decreased significantly from 51 (43, 56) to 33 (27, 43.8) mmHg (P < 0.001) and from 864 (680, 1128) to 520 (392, 808) dyn·s⁻¹·m⁻⁵ (P < 0.001), respectively, while the heart rate reduced from 89 (74, 94) to 82 (72, 88) (P = 0.023). However, the improvement in CO was not statistically significant. Echocardiographic results showed an increase in tricuspid annular plane systolic excursion (TAPSE) from 14.0 ± 3.1 to 16.6 ± 3.9 mm (P < 0.001), a reduction in tricuspid regurgitation pressure gradient (TRPG) from 81.5 ± 24.3 to 63.6 ± 31.1 mmHg (P < 0.001), and a decrease in the right ventricular internal diameter/end-diastolic diameter of the left ventricle (RV/LV) ratio from 1.2 (1.0, 1.4) to 0.89 (0.74, 1.02) (P < 0.001).

Figure 1

The change of (A) 6MWD, (B) mPAP, (C) PVR, (D) PCS along with BPA procedures. It shows that with the process of BPA, hemodynamics improved gradually. 6MWD: 6-min walk distance, mPAP: mean pulmonary arterial pressure, PVR: pulmonary vascular resistance, PCS: physical component summary, BPA: balloon pulmonary angioplasty. ^*P < 0.05, ^**P < 0.001.

Improvements in QoL scores also were seen after BPA, with the PCS and MCS scores increasing significantly from 30.4 ± 9.9 to 69.7 ± 18.5 and from 46.4 ± 19.0 to 81.6 ± 13.2 (both P < 0.001), respectively. The PF, RP, BP, GH, VT, SF, RE, and MH scores also increased significantly (Figure 2).

Figure 2

The changes in QoL before and after BPA. QoL: quality of life, BPA: balloon pulmonary angioplasty, PF: physical functioning, BP: bodily pain, GH: general health, RE: role-emotional, RP: role-physical, SF: social functioning, VT: vitality, MH: mental health, PCS: physical component summary, MCS: mental component summary.

Comparison of clinical characteristics according to the PCS score at baseline and after therapy

ROC analysis showed that 35 was the cutoff value before treatment, and patients who had a PCS score of ≥35 at baseline had longer 6MWD (429 vs. 327 m, P = 0.03), lower NT-proBNP level (265.5 vs. 2362 pg/mL, P = 0.002), lower PVR (716 vs. 1009 dyn·s⁻¹·m⁻⁵, P = 0.009), lower right arterial pressure (RAP; 5 vs. 9 mmHg, P = 0.02), lower right ventricular diameter (RVD; 43 vs. 50 mm, P = 0.019), lower RV/LV ratio (0.97 vs. 1.31, P = 0.005), higher TAPSE (15.9 vs. 13 mm, P = 0.005), greater CO (4.4 vs. 3.6 L/min, P = 0.028), and higher CI (2.5 vs. 2.1 L min⁻¹ m⁻², P = 0.039) (Table 3).

In addition, a PCS score of 46 was set as the cutoff value after therapy according to ROC analysis (Appendix Figure). Patients who had a PCS of >46 after BPA had better 6MWD (463 vs. 287 m, P = 0.047), CO (3.83 vs. 3.28 L/min, P = 0.031), CI (2.47 vs. 1.71 L min⁻¹ m⁻², P = 0.006), and PVR (594.36 vs. 910.00 dyn·s⁻¹·m⁻⁵, P = 0.048) (Table 4).

Correlation between QoL improvement and clinical or hemodynamic improvements after BPA

There was no linear dependence between the change in QoL and clinical or hemodynamic improvement after BPA for these patients. Besides, 19 patients (55.9%) who had already got a better PCS (>46) after treatment did not achieve the goal of mPAP <P30 mmHg after BPA (Figure 3). For patients who underwent more than four sessions of BPA, the 6MWD, mPAP, and PVR improved gradually with each additional BPA session; however, the PCS score improved more rapidly than the other parameters.

Figure 3

The different changes of PCS and mPAP before and after BPAs. It demonstrated that after four sessions of BPA, 19 patients (55.9%) who had a better PCS (PCS ≥ 46) after treatment still did not achieve the goal of a mPAP ≤30 mmHg. PCS: physical component summary, mPAP: mean pulmonary arterial pressure, BPA: balloon pulmonary angioplasty.

Changes in hemodynamics and PCS score during follow-up

During a follow-up period of 4–6 months after the last BPA procedure, 20 patients underwent RHC. For these 20 patients, the mPAP increased slightly from 35 (31, 48) to 38 (27, 45) mmHg between the last BPA and the last follow-up, while the RAP changed from 5 (4, 7) to 4 (3, 5) mmHg and the CO increased from 3.8 (3.6, 4.2) to 4.2 (3.8, 4.7) L·min⁻¹. However, these differences were not significant. Additionally, the PCS score of these patients did not improve significantly from the last BPA procedure to the final follow-up (68.5 vs. 71.3, P = 0.287). PVR was the only parameter to show significant improvement during follow-up, with a decrease from 659.6 ± 331.5 to 538.3 ± 266.4 dyn·s⁻¹·m⁻⁵ (P = 0.045; Figure 4).

Figure 4

The trend of (A) CO, (B) PVR, (C) mPAP, and (D) PCS from baseline to follow-up of 20 patients who had 4–6 months of follow-up. It demonstrated that PVR still improved in the follow-up, while PCS tended to be stable. PCS: physical component summary, CO: cardiac output, PVR: pulmonary vascular resistance, mPAP: mean pulmonary arterial pressure. ^#P > 0.05, ^*P < 0.05, ^**P < 0.001.