Abstract
Background:
Inhaled iloprost (average >30 µg/d) has been considered an effective treatment for severe pulmonary hypertension (PH). Further evidence also showed that low‐dose iloprost given intravenously was equally effective as high‐dose iloprost in the therapy of systemic sclerosis.
Hypothesis:
Patients with pulmonary hypertension will benefit from inhalation of low‐dose iloprost.
Methods:
Sixty‐two patients with PH were enrolled and initiated with neubulizedlow‐dose iloprost (2.5 µg per inhalation, 6× daily) for 24 weeks in 13 medical centers in China. Efficacy endpoints included changes in 6‐minute walk distance (6MWD), World Health Organization functional class (WHO‐FC), and hemodynamic parameters.
Results:
Fourteen patients (22.6%) prematurely discontinued the study: 8 due to clinical worsening (6 in WHO‐FCIII–IV at baseline), 4 because of protocol change, and 2 patients lost during follow‐up. In the remaining 48 patients, 6MWD was increased from 356 ± 98 meters to 414 ± 99 meters (P < 0.001) and WHO‐FC improved significantly (P = 0.006) after 24‐week inhalation therapy. Cardiac output, cardiac index, and mixed venous oxygen saturation improved significantly compared with baseline (n = 34, P < 0.05). Most of the hemodynamic parameters improved significantly in patients in WHO‐FC II (P < 0.05) but not in patients in WHO‐FCIII–IV.
Conclusions:
Low‐dose iloprost inhalation significantly improved exercise capacity and functional status in patients with PH. It was well tolerated. The improvement of hemodynamics was confirmed in patients with WHO‐FCI–II but not in patients with WHO‐FCIII–IV, suggesting the importance of early treatment in patients with advanced disease stages. Clin. Cardiol. 2012 DOI: 10.1002/clc.21987
This study was supported by National Grant from the Ministry of Science and Technology (Beijing, China, project number 2006BAI01A07) and the Capital Development Scientific Fund (Beijing, China, project number 2005‐1018). The authors have no other funding, financial relationships, or conflicts of interest to disclose.
Introduction
Pulmonary hypertension (PH) is a hemodynamic and pathophysiological state that can be found in multiple clinical conditions. It has been defined as an increase in mean pulmonary arterial pressure ≥25 mm Hg at rest as assessed by right‐heart catheterization.1Precapillary PH refers to the values of pulmonary wedge pressure ≤15 mm Hg. Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are the common and most investigated forms of precapillary PH.
The impaired production of prostacyclin, reflecting the endothelial dysfunction of remodeled pulmonary arteries that plays the key pathobiological role in PH,2 represents the rationale for the exogenous therapeutic administration of prostacyclin and prostanoids.3, 4, 5 loprost is a chemically stable derivative of prostacyclin with similar biologic properties but with a longer half‐life. The clinical efficacy of inhaled high‐dose iloprost (5.0 µg per inhalation, average >25–30 µg/d) in patients with severe PH has been demonstrated in previous randomized, double‐blind, placebo‐controlled studies6, 7 and in open‐label uncontrolled studies.8, 9, 10, 11, 12 However, a dose‐dependent efficacy of inhaled iloprost has not been tested so far on PH. Interestingly, a study using low‐dose iloprost (0.5 ng/kg/min) intravenously demonstrated equal effectiveness as the high dose (2 ng/kg/min) in the long‐term treatment of systemic sclerosis.13 Therefore, we wondered whether patients with PH would also benefit from inhaled low‐dose iloprost. The purpose of this open‐label study was to investigate the effects of inhaled low‐dose iloprost for 24‐week treatment in patients with PH.
Methods
Selection of Patients
Adult patients with PAH or inoperable CTEPH were enrolled in this study, which was similar to the Aerosolized Iloprost Randomized Study.6 PAH was defined as the presence of precapillary PH (mean pulmonary arterial pressure ≥25 mm Hg and pulmonary wedge pressure ≤15 mm Hg at rest as assessed by right‐heart catheterization) in the absence of other causes of precapillary PH, such as PH due to lung disease, CTEPH, or other rare diseases.1 Patients with PAH associated with congenital heart disease were enrolled if they had persistent PAH at 2 years after surgical or interventional repair, or if they were not eligible for surgical or interventional treatment. The diagnosis of CTEPH was based on the same hemodynamic findings as PAH in patients with multiple chronic/organized occlusive thrombi/emboli in the main, lobar, segmental, or subsegmental pulmonary arteries. Patients were considered to have inoperable CTEPH if they were not amenable to pulmonary endarterectomy due to peripheral localization of thrombotic material (according to pulmonary angiography) that was surgically inaccessible. Each CTEPH case was evaluated by a qualified surgeon and inoperability was confirmed before enrollment.
The inclusion criteria included (1) patient age 18–65 years; (2) not responsive to acute vasodilator testing; and (3) 100–450‐meter baseline 6‐Minute Walk Distance (6MWD). The main exclusion criteria were (1) a history or suspicion of inability to cooperate adequately; (2) PH due to left‐heart disease, lung disease/hypoxia, or miscellaneous diseases (Venice 2003 classification); (3) a forced expiratory volume in 1 second to forced vital capacity ratio <50%, a total lung capacity <60% of predicted normal value; (4) current treatment with PAH‐specific drug therapy (prostanoids, endothelin‐receptor antagonists, phosphodiesterase type‐5 inhibitors, and L‐arginine) or calcium channel blockers for <3 months; (5) inability to perform the 6‐Minute Walk Test; (6) a history of bleeding diathesis or gastrointestinal and intracranial bleeding within 6 months, or other diseases with a high risk of bleeding; (7) serum hepatic aminotransferases ≥3× upper limit of normal or serum creatinine ≥450 µmol/L; (8) other cardiac or cerebral vascular disease, including serious cardiac arrhythmias, unstable angina pectoris, myocardial infarction within 6 months, and transient ischemia attack or stroke within 3 months; (9) systemic arterial pressure <90/50 mm Hg or uncontrolled hypertension (>170/110 mm Hg); and (10) pregnancy or breastfeeding. This study complied with the Declaration of Helsinki and was approved by the local institutional ethics review boards at all participating centers. Written informed consents were obtained from all patients.
Study Design
This was a 24‐week, prospective, open‐label trial conducted in 13 medical centers in China between April 2007 and August 2010. On the basis of conventional therapy (digoxin, oral anticoagulants, and diuretics), all patients received iloprost (Ventavis, Bayer Schering Pharma, Germany) inhalation using a low dose (2.5 µg per inhalation, 6× daily) for 24 weeks. Iloprost was inhaled with the PARI LC Star nebulizer (PARI GmbH, Starnberg, Germany) driven by a PARI TurboBoy‐N compressor (PARI GmbH) for 15 minutes. The initial dose of inhalation was 2.5 µg; if tolerated, the dose was maintained for chronic therapy. The frequency of inhalation was titrated up to 6–9× daily with an overnight break, determined individually according to severity of illness, tolerability, and patient compliance.
Outcome Measures
The primary efficacy index of the present study was defined as the change in 6MWD during 24‐week inhalation therapy. Changes in World Health Organization functional class (WHO‐FC) and hemodynamic parameters derived from right‐heart catheterization were used as secondary efficacy indices. Follow‐up visits were conducted every month after initiation of inhaled iloprost. Both 6MWD and WHO‐FC were assessed on patients both at baseline and after 24‐week treatment. The 6‐Minute Walk Test was performed according to American Thoracic Society guidelines.14 All patients underwent right‐heart catheterization at baseline, and in some patients the hemodynamics were re‐evaluated after treatment. Cardiac output was determined using the thermodilution technique or calculated according to the Fick method.
Safety
Safety and tolerability were evaluated by serial monitoring of adverse effects and clinical deterioration. All adverse effects were recorded during telephone contact or clinic appointments. Clinical deterioration was defined as initiation of other PAH‐specific drug therapy, up‐titration of iloprost dose, lung or heart‐lung transplant, and death.
Statistical Analysis
Continuous variables were reported as mean ± SD or median (range). Qualitative variables were reported as frequencies and percentages. No imputation for missing values was used. Continuous variables were compared using the paired t test, whereas qualitative variables were compared using the test for significance of proportion. All reported P values were 2‐sided. A P value <0.05 was considered statistically significant. Statistical analysis was performed using the SPSS 11.5 statistical package (SPSS Inc., Chicago, IL).
Results
Baseline Characteristics of Patients
A total of 62 patients with PH (idiopathic PAH, n = 24; PAH associated with congenital heart disease, n = 18; PAH associated with connective‐tissue disease, n = 13; and inoperable CTEPH, n = 7) were enrolled. The mean age was 38 ± 11 years and the majority of patients (79%) were female. Ninety‐five percent of patients were in WHO‐FC classes II and III. Baseline characteristics of the 62 patients are described in Table 1. The baseline 6MWD and hemodynamic parameters indicated a moderate severity of PH.
Table 1.
Demographic and Baseline Characteristics
| Age, y | 38 ± 11 |
| Sex | |
| M | 13 (20.97) |
| F | 49 (79.03) |
| Cause of PH | |
| Idiopathic | 24 (38.71) |
| Congenital heart disease | 18 (29.03) |
| Connective‐tissue disease | 13 (20.97) |
| CTEPH | 7 (11.29) |
| BMI, kg/m2 | 20.80 ± 3.66 |
| Systolic arterial pressure, mm Hg | 113 ± 15 |
| Heart rate, bpm | 83 ± 11 |
| WHO‐FC | |
| I | 1 (1.61) |
| II | 29 (46.77) |
| III | 30 (48.39) |
| IV | 2 (3.23) |
| 6MWD, m | 348 ± 102 |
| Borg Dyspnea score | 3.2 ± 2.0 |
| Laboratory variables | |
| Mixed venous oxygen saturation,%a | 65.3 ± 10.1 |
| Systemic arterial oxygen saturation, %a | 93.8 ± 6.1 |
| Hemodynamic variables | |
| Mean pulmonary artery pressure, mm Hg | 63 ± 17 |
| Cardiac output, L/mina | 3.91 ± 1.36 |
| Cardiac index, L/min/m2 a | 2.50 ± 0.89 |
| PVR, dyn.sec.cm−5a | 1314 ± 732 |
| PWP, mm Hg | 8 ± 4 |
Abbreviations: PH, pulmonary hypertension; CTEPH, chromic thromboembolic pulmonary hypertesionm 6MWD, 6‐Minute Walk Distance; BMI, body mass index; F, female; M, male; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; PWP, pulmonary wedge pressure; WHO‐FC, World Health Organization functional class. Values are presented as mean ± SD or n (%).
Data on all variables were available for all patients except in the following categories: 57 patients in cardiac output, 57 patients in cardiac index, 57 patients in PVR, 48 patients in mixed venous oxygen saturation, 54 patients in systemic arterial oxygen saturation.
All patients received low‐dose iloprost therapy by each inhalation of 2.5 µg on the basis of optimal conventional therapy. The mean frequency of inhalation was 6× daily, ranging from 4× to 8×, corresponding to a mean inhaled dose of 15 µg per day. During the follow‐up, 48 patients (77.4%) completed the full 24 weeks of inhalation therapy. Fourteen patients discontinued the study, including 8 patients with clinical deterioration, 4 patients who changed the protocol because of poor compliance, and 2 patients who missed follow‐up. Among patients with clinical deterioration, 6 were in WHO‐FC III or IV at baseline.
Effects of Iloprost on 6‐Minute Walking Distance, Borg Dyspnea Score, World Health Organization Functional Class, Systemic Arterial Oxygen Saturation, and Systemic Arterial Pressure
The results of the 6MWD, Borg Dyspnea score, systemic arterial oxygen saturation, and systemic arterial pressure at baseline and after 24 weeks' application of iloprost are shown in Table 2. Compared with baseline, 6MWD increased significantly, by 57 meters (95% confidence interval [CI]: 26.59–87.82 m, P < 0.001). According to post‐hoc analysis, the type of PH had no significant effect on the improvement of 6MWD. In the meantime, there was a significant decrease in Borg Dyspnea score compared with that in baseline (P = 0.010). The WHO‐FC was improved significantly in general (P = 0.006; Figure 1), including ≥1 class improvement in 14 patients, unchanged in 31 patients, and worsened in 3 patients. On the other hand, the systemic arterial oxygen saturation and systemic arterial pressure remained comparable with baseline values.
Table 2.
Exercise Capacity, Functional Status, Arterial Oxygen Saturation, and Mean Systemic Arterial Pressure at Baseline and After 24 Weeks of Treatment
| Parameter | Baseline | Week 24 | Changesa | P Value |
|---|---|---|---|---|
| Systolic arterial pressure, mm Hg | 112 ± 15 | 112 ± 13 | −0.17 (−3.94, 3.61) | 0.930 |
| Heart rate, bpm | 83 ± 11 | 80 ± 9 | −2.66 (−5.96, 0.64) | 0.112 |
| 6MWD, m | 356 ± 98 | 414 ± 99 | 57.2 (26.59, 87.82) | <0.001 |
| Borg Dyspnea score | 2.9 ± 1.8 | 2.3 ± 1.7 | −0.56 (−0.98, −0.12) | 0.010 |
| Systemic arterial oxygen saturation, %b | 93.2 ± 3.9 | 93.5 ± 3.8 | 0.36 (−0.86, 1.56) | 0.552 |
Abbreviations: 6MWD, 6‐Minute Walk Distance; CI, confidence interval.
Changes are in the form of mean (95% CI).
Data on systemic arterial oxygen saturation were available for 27 patients.
Figure 1.
Changes in WHO‐FC from baseline to 24 weeks later. Abbreviations: WHO‐FC, World Health Organization functional class.
Effects of Iloprost on Hemodynamic Parameters
The hemodynamics of 34 of 48 patients who completed the study were re‐evaluated after 24 weeks of low‐dose iloprost therapy. The results are shown in Table 3. Cardiac output, cardiac index, and mixed venous oxygen saturation were improved significantly after 24‐week inhalation therapy (P = 0.025, P = 0.035, and P = 0.036, respectively). By contrast, the mean pulmonary arterial pressure and pulmonary vascular resistance were mainly unchanged after therapy. The baseline characteristics were well matched between the patients in whom the hemodynamics were re‐evaluated and the patients in whom they were not.
Table 3.
Changes in Hemodynamic Parameters During 24 Weeks of Inhalation Low‐Dose Iloprost
| Parameters | Baseline | Week 24 | Changesa | P Value |
|---|---|---|---|---|
| Mean pulmonary arterial pressure, mm Hg | 63 ± 16 | 60 ± 15 | −2.44 (−5.66, 0.78) | 0.132 |
| Cardiac output, L/min | 4.16 ± 1.51 | 4.69 ± 1.65 | 0.53 (0.07, 0.99) | 0.025 |
| Cardiac index, L/min/m2 | 2.73 ± 1.00 | 3.06 ± 1.08 | 0.33 (0.02, 0.63) | 0.035 |
| PVR, dyn·sec·cm−5 | 1244.9 ± 804 | 1051.1 ± 649 | −193.88 (−409.80, 22.05) | 0.077 |
| PWP, mm Hg | 8.8 ± 4.1 | 8.45 ± 3.5 | −0.30 (−1.73, 1.13) | 0.671 |
| Mixed venous oxygen saturation, %b | 65.4 ± 9.5 | 68.2 ± 10.8 | 2.81 (0.20, 5.41) | 0.036 |
Abbreviations: CI, confidence interval; PVR, pulmonary vascular resistance; PWP, pulmonary wedge pressure.
Changes are in the form of mean (95% CI).
Data on mixed venous oxygen saturation were available for 27 patients.
Subgroup Analysis Between World Health Organization Functional Classes II and III–IV
Thirty‐four patients were classified into 2 subgroups according to their baseline WHO‐FC (14 patients in the WHO‐FC II subgroup and 20 patients in the WHO‐FCIII–IV subgroup). After low‐dose iloprost therapy for 24 weeks, 6MWD increased by 59 meters in the WHO‐FC II subgroup (95% CI: 14.67‐103.95 m, P = 0.013) and by 84 meters in the WHO III–IV subgroup (95% CI: 42.26‐125.63 m, P = 0.001). The increased distances between the 2 subgroups were similar (P = 0.409). However, after 24‐week inhalation therapy, the mean pulmonary arterial pressure, cardiac output, cardiac index, pulmonary vascular resistance, and mixed venous oxygen saturation were all improved significantly in the WHO‐FC II subgroup (P < 0.05) but not in the WHO‐FCIII–IV subgroup (P > 0.05), as shown in Table 4.
Table 4.
Hemodynamic Parameter Changes During 24‐Week Treatment Between WHO‐FC II and III–IV
| WHO‐FC II | WHO‐FC III–IV | |||
|---|---|---|---|---|
| Baseline | Changesa | Baseline | Changesa | |
| Mean pulmonary arterial pressure, mm Hg | 65 ± 20 | −6.79 (−11.16, −2.41)b | 60.70 ± 12.62 | 0.60 (−3.71, 4.91)c |
| Cardiac output, L/min | 4.51 ± 1.79 | 0.94 (0.07, 1.81)d | 3.92 ± 1.28 | 0.24 (−0.28, 0.76) |
| Cardiac index, L/min/m2 | 2.85 ± 1.07 | 0.63 (0.08, 1.18)d | 2.65 ± 0.96 | 0.11 (−0.24, 0.46) |
| PVR, dyn·sec·cm−5 | 1331 ± 1027 | −428 (−842.11, −13.82)d | 1185 ± 627 | −30.01 (−261.44, 201.41) |
| PWP, mm Hg | 6.09 ± 3.33 | 0.64 (−1.72, 2.99) | 10.32 ± 3.80 | −0.84 (−2.77, 1.08) |
| Mixed venous oxygen saturation, %e | 66.51 ± 8.38 | 6.20 (2.22, 10.17)b | 64.56 ± 10.48 | 0.09 (−3.05, 3.24)c |
Abbreviations: PVR, pulmonary vascular resistance; PWP, pulmonary wedge pressure; WHO‐FC, World Health Organization functional class.
Changes are in the form of mean (95% confidence interval) from baseline to 24‐week therapy.
P < 0.01 for the difference from baseline values.
P < 0.05 for the difference compared with the changes in the WHO FC II subgroup.
P < 0.05 for the difference from baseline values.
Data on mixed venous oxygen saturation were available for 12 patients and 15 patients in WHO‐FC II and WHO‐FC III–IV, respectively.
Safety
Thirteen patients reported 29 adverse effects during the study period. Eight patients experienced ≥1 adverse effect. The adverse effects included flushing (n = 10), cough (n = 6), hypotension (n = 4), headache (n = 4), anorexia (n = 3), abdominal distension (n = 1), and chest distress (n = 1). Most adverse effects were mild to moderate in intensity and generally subsided within several days of the initiation of inhalation. However, anorexia, abdominal distension, and chest distress were relatively serious and even lasted for months, and limited the daily inhalation times. None of these adverse effects resulted in cessation of the study protocol. Among 8 patients with clinical deterioration, 4 patients died due to right‐heart failure and 3 patients manifested symptoms of right‐ventricular failure so that up‐titration of iloprost dose or commencement of combination therapy was needed, and 1 patient underwent a lung transplant.
Discussion
This study demonstrated that low‐dose iloprost inhalation (average 15 µg/d) for 24 weeks significantly improved exercise capacity, functional status, and pulmonary hemodynamics in patients with PH in general. Subgroup analysis revealed that the hemodynamics were improved significantly in patients in WHO‐FC II but not in patients in WHO‐FCIII–IV; even the 6MWD was markedly increased in this advanced patient subgroup. It suggested the importance of treating patients in earlier disease stages, choosing a higher iloprost dose, or pursuing more aggressive therapy strategies in patients with advanced disease.
Six‐minute walk distance has been widely used as a primary index to measure the treatment effect in most clinical trials related to PH.6, 15, 16, 17 Our data showed that inhalation of low‐dose iloprost for 24 weeks significantly improved exercise capacity, by an 83‐meter increase in 6MWD in patients in WHO‐FCIII–IV, similar to the 75–85‐meter improvement in a previous study.10 Interestingly, the functional status and hemodynamic parameters (mixed venous oxygen saturation, cardiac output, and cardiac index) were improved as much as the improvement observed in patients receiving high‐dose iloprost inhalation.12, 18, 19, 20
To date, many published studies have focused on the long‐term effects of iloprost in patients with PH. The outcomes of iloprost monotherapy regarding hemodynamic improvement were conflicting, which might be due to the variety of types of PH, different disease stages, and inconsistent observation periods among those uncontrolled clinical trials.10, 12, 18, 21, 22, 23 In the AIR study, despite improved 6WMD and functional class, the hemodynamics did not change significantly in patients treated with high‐dose iloprost for 12 weeks compared with baseline.6 The notable clinical benefit might be attributable to both an improvement in the iloprost group and a deterioration in the placebo group.24 The findings were similar in advanced patients in our study; 6MWD and WHO‐FC improved without changing the hemodynamics in patients in WHO‐FCIII–IV. Although iloprost has become the treatment of choice in patients with severe PAH, there was evidence to suggest that earlier use of iloprost might also benefit patients with mild to moderate PH.
All large published studies implicated hemodynamics as an important predictor for survival in patients with PH.25, 26, 27 Because of the negative effect of low‐dose iloprost on hemodynamics in our patients in WHO‐FCIII–IV, which might be due to more resistance to therapy, the survival rate might not be improved in our study. Meanwhile, iloprost combined with bosentan or sildenafil has been proven as an effective treatment strategy.7, 28 Combination therapy with other PAH‐specific drugs, increasing the inhaled iloprost dose, or treating at an earlier disease stage might bring on additional hemodynamic benefit and lead to a better prognosis.
In addition, our study showed that inhalation of low‐dose iloprost was well tolerated. Flushing, cough, hypotension, and headache were the common side effects, and the rate of side effects was lower than that in studies with high‐dose iloprost inhalation.6, 11, 20 No patient discontinued the study due to severe adverse effects. The percentages of deterioration and death were comparable with those in other studies (12.9% vs 25%–27.3%).12, 18 The clinical deterioration was serious in 8 patients; low‐dose iloprost did not show an adequate treatment effect on those patients. The baseline characteristics of 14 patients who refused to re‐evaluate the hemodynamics were similar as those of 34 patients who underwent right‐heart catheterization after 24 weeks of treatment, indicating that the missing hemodynamic data of these 14 patients might not create systemic bias in the present study.
There were several limitations to the present study. The data of 8 patients with clinical deterioration were not included in the analysis; this might overestimate the outcomes. The other limitation was the small sample size and the heterogeneity of the study population. However, inclusion of various types of PH in our study provided new information regarding the effects of low‐dose iloprost. Further randomized study would be needed to reveal the dose‐dependent effects and to determine the optimal dosage of inhaled iloprost in the treatment of PH.
Conclusion
Low‐dose iloprost inhalation significantly improved exercise capacity and functional status in patients with PH. It was well tolerated and the rate of side effects was lower than that reported with high‐dose iloprost. The improvement of hemodynamics was confirmed in patients in WHO‐FCI–II but not in patients in WHO‐FCIII–IV, suggesting the importance of early treatment in patients with advanced disease.
Acknowledgements
Yun‐Juan Sun prepared the primary manuscript. Guang‐Liang Shan, Yun‐Juan Sun, and Wei‐Jie Zeng analyzed data. Chang‐Ming Xiong, Qing Gu, Xian‐Ling Lu, and Feng Zhu collected data. Jian‐Guo He led the project as principal investigator. The authors assume full responsibility for the completeness and accuracy of the content of the manuscript. The authors thank Professor Jie‐Lin Pu for technical assistance in the preparation of this manuscript.
The authors acknowledge the study group participants, not listed as authors: Da‐Xin Zhou, MS, Zhongshan Hospital, Fudan University, Shanghai, China; An‐Kang Lv, MD, Shanghai Ruijin Hospital, Shanghai, China; Zai‐Xin Yu, MD, Xiangya Hospital Central‐South University, Hunan, China; Hua Cao, MD, First Affiliated Hospital of Fujian Medical University, Fujian, China; Yi‐Gao Huang, BSMed Guangdong General Hospital and Guangdong Cardiovascular Institute, Guangdong, China; Jie‐Yan Shen, MS, and Chun‐De Bao, MD, Renji Hospital, Shanghai, China; Yuan‐Hua Yang, MD, Beijing Chao‐Yang Hospital, Beijing, China; Bing‐Xiang Wu, MD, First Affiliated Hospital, Harbin Medical University, Heilongjiang, China; Meng‐Tao Li, MD, Peking Union Medical College Hospital, Beijing, China; Rong Yang, MD, Jiangsu Province People's Hospital, Jiangsu, China; Zhen‐Wen Yang, MD, Tianjin Medical University General Hospital, Tianjing, China; and Zhao‐Zhong Cheng, MS, The First Affiliated Hospital, Qingdao Medical University, Shandong, China.
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